The epidermal growth factor receptor (EGFR) is among the most frequently mutated genes in lung adenocarcinomas (LUAC). The combination of afatinib and bevacizumab has primarily been reported in LUAC cases exhibiting resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), particularly in classical variants such as EGFR exon 19 deletions and the L858R mutation in exon 21. However, the clinical efficacy of afatinib combined with bevacizumab in treating rare EGFR mutations remains underexplored.

We present a case of T4N0M0 stage IIIA LUAC in which disease progression occurred following tumor resection and subsequent chemotherapy combined with bevacizumab. Next-generation sequencing of peripheral blood identified a novel and rare EGFR exon 20 Q787L mutation. Maintenance therapy with icotinib, a first-generation EGFR-TKI, combined with bevacizumab was initiated, but the patient developed resistance to icotinib after 8 months. No drug availability variants or acquired resistance-related mutations were detected. Subsequently, maintenance therapy with oral afatinib plus bevacizumab was initiated, resulting in partial remission after 3 months. As of the most recent CT scan in November 2023, the patient has achieved a progression-free survival (PFS) of 56 months on afatinib plus bevacizumab maintenance therapy, representing the longest reported duration to date, with no severe side effects observed.

Our findings suggest that the combination of afatinib and bevacizumab may offer long-term clinical benefits for LUAC patients harboring the novel and rare EGFR Q787L mutation. This case highlights a potential therapeutic strategy warranting further investigation in clinical studies.

The expression of programmed cell death-ligand 1 (PD-L1) and mutation in epidermal growth factor receptor (EGFR) are biomarkers used for perioperative treatment of lung adenocarcinoma. However, the clinical significance of PD-L1 expression in surgically resected EGFR-mutant lung adenocarcinoma remains unclear. We conducted a real-world database of patients with surgically resected lung adenocarcinoma from 2015 to 2018 was constructed across 21 centers in Japan. The association among PD-L1 expression, EGFR mutations, and prognosis was evaluated. Among 847 patients, PD-L1 expression was negative (tumor proportion score [TPS] < 1%) in 429 (51%), weakly positive (TPS = 1%-49%) in 275 (32%), and strongly positive (TPS ≥50%) in 143 (17%) patients. EGFR mutations were detected in 331 (39%) patients. PD-L1 expression was associated with poor recurrence-free survival (RFS) (p < .001) in both EGFR-mutant and wild-type patients. However, in EGFR-mutant patients, PD-L1 expression was not associated with overall survival (OS) (p = .506). Multivariable analysis confirmed an association between PD-L1 expression and RFS but not OS. Furthermore, in EGFR-mutant patients treated with EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment post-relapse, PD-L1 expression was not associated with overall response rate (p = .714), disease control rate (p = .554), or progression-free survival (p = .660). In conclusion, PD-L1 expression predicted poor RFS-independent EGFR status but did not show any association with OS in EGFR-mutant patients. The efficacy of post-relapse EGFR-TKI treatment was independent of PD-L1 expression. The significance of PD-L1 expression in perioperative EGFR-TKI therapy should be evaluated.

Tumor microvasculature is an important component of the tumor microenvironment (TME), and it has been reported that tumor microvasculature induces TME to become immunosuppressive via vascular endothelial growth factor. However, the significance of this in adenocarcinoma with epidermal growth factor receptor (EGFR) common mutations has not been fully investigated.

We analyzed 262 patients with adenocarcinoma harboring EGFR common mutations who underwent surgery at Kyushu University Hospital between 2006 and 2021. Microvessel density (MVD) was calculated by CD34 immunohistochemistry. Patients were categorized into high and low MVD status, which was compared with the clinicopathological characteristics.

A total of 136 (51.9%) patients had L858R mutation, and 126 (48.1%) had Exon 19 Del. Regarding MVD status; 133 patients (50.8%) were classified as high and 129 (49.2%) as low. Fisher's exact test revealed a significant association of high MVD status with high CD8+ tumor infiltrating lymphocytes (TILs) (p = 0.0187), low GZMB+ TILs (p = 0.0019), and high Foxp3+ TILs (p = 0.0003). On multivariate analysis, MVD status was significantly associated with Foxp3+ TILs and GZMB+ TILs. Fisher's exact test also revealed that tumors with L858R mutation had a high MVD status (p = 0.0136) compared with tumors with deletions of exon 19 (Exon 19 Del), and multivariate analysis revealed that L858R mutation was significantly associated with high MVD status.

In adenocarcinomas harboring EGFR common mutations, abundant tumor microvasculature might induce the TME to be immunosuppressive. Tumors with L858R mutation compared with Exon 19 Del might be more likely to form an immunosuppressive TME owing to the abundance of tumor microvasculature.

Accurate diagnosis and staging are essential for optimizing lung cancer management. The 9th edition of the TNM classification emphasizes distinguishing between single-station and multi-station N2 disease, highlighting the necessity of comprehensive mediastinal node assessment for clinical staging. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive modality used for nodal staging and diagnosis of lung cancer, offering a diagnostic yield comparable to that of mediastinoscopy when performed by experts. Additionally, EBUS-TBNA facilitates essential ancillary testing, including next-generation sequencing (NGS)-based biomarker panels and PD-L1 immunohistochemistry, which are critical for evaluating the suitability of targeted therapies and immune checkpoint inhibitors. Notably, advancements in perioperative management, such as neoadjuvant and adjuvant therapies with immunotherapy and targeted agents, have improved the outcomes of locally advanced diseases. EBUS-TBNA helps identify patients with early-stage lung cancer who are candidates for perioperative therapy.

This review discusses lung cancer diagnosis, nodal staging, the 9th TNM classification, biomarker testing, PD-L1 immunohistochemistry, and precision medicine.

Lung cancer management requires pathological diagnosis, including histological subtyping, accurate nodal staging of the hilum and mediastinum, and NGS-based biomarker and PD-L1 testing. EBUS-TBNA achieves all three in a single session, making it indispensable in modern lung cancer care.

The T790M secondary mutation in EGFR confers therapeutic resistance to EGFR-TKIs, leading to poor outcomes. Non-small-cell lung cancer (NSCLC) harboring EGFR T790M mutation is incurable and there is an urgent need for improved therapeutics. Here we report the identification of a small compound, MG-3C, that kills NSCLC cells with T790M mutation while sparing lung cancer cells without T790M mutation. We found that MG-3C activity targets EGFR-STAT3 signaling pathway in NSCLC through direct inhibition of matrix metalloproteinase 9 (MMP-9), ultimately leading to G2/M phase arrest, growth inhibition and apoptosis. Compared with the reported MMP-9 inhibitor Ilomastat, MG-3C shows high anticancer activity and affinity for targets. MG-3C forms hydrogen bonds with the ASP-113, ASP-201 and HIS-203 amino acid residues of MMP-9 with a docking fraction of -9.04 kcal/mol, while Ilomastat forms hydrogen bonds with the GLN-169, ASP-201 and HIS-203 amino acid residues of MMP-9 with a docking fraction of -5.98 kcal/mol. The spatial structure composed of ASP-113, ASP-201, and HIS-203 of MMP-9 provides a new coordinate for the design of MMP-9 inhibitors. Most importantly, subcutaneous and oral administration of MG-3C elicit dramatic regression of NSCLC xenograft tumors harboring T790M mutation as well as favorable biosafety profile in vivo, suggesting that MG-3C may be a potential candidate for NSCLC harboring T790M mutation.

Small molecules targeting activating mutations within the epidermal growth factor receptor (EGFR) are efficacious anticancer agents, particularly in non-small cell lung cancer (NSCLC). Among these, lazertinib, a third-generation tyrosine kinase inhibitor (TKI), has recently gained FDA approval for use in combination with amivantamab, a dual EGFR/MET-targeting monoclonal antibody. This review delves into the discovery and development of lazertinib underscoring the improvements in medicinal chemistry properties, especially in comparison with osimertinib. Analysis of its structure-activity relationships (SAR), as outlined in the patent literature, reveals the structural diversity explored enroute to the candidate molecule. The resulting structure of lazertinib is distinguished among other TKIs due to the combination of the hydrophobic phenyl and hydrophilic amine substituents on the pyrazole. The structural basis for the selectivity against the T790M mutation is enabled by the substituted pyrazole moiety, which facilitates both van der Waals and H-bonding interactions with the EGFR kinase domain. Insights from this case study offer lessons that can inform the future design of kinase inhibitors with improved safety and efficacy profiles for cancer treatment and other diseases.

Recent advances in molecular oncology have increasingly illuminated the role of germline EGFR mutations in non-small cell lung cancer (NSCLC). This case report presents the presence of a unique familial occurrence of EGFR mutations in patients with NSCLC.

A mother and son, both never-smokers of Caucasian ethnicity, were diagnosed with advanced metastatic lung adenocarcinoma. In one patient, tumor molecular analysis by next generation sequencing (NGS) identified two EGFR mutations: the activating mutation c.2573T > G; p.Leu858Arg (p.L858R) in exon 21 of the EGFR gene, and the somatic non-pathogenic mutation c.2612 C > A; p.Ala871Glu (p.A871E) in exon 21 of the EGFR gene. The second patient also harbored the same two EGFR mutations. The patient underwent genetic testing which revealed the germline origin of the A871E mutation. Whether the presence of this mutations was associated with increased predisposition to cancer has yet to be determined. Our case report highlights the need for further exploration of the role of germline mutations, including the A871E mutation, in tumorigenesis and its implications for treatment response and inheritance patterns.

The investigation and comprehension of the significance of each individual EGFR mutation hold the promise for potential in cancer prevention or early diagnosis within family cohorts and understanding the mechanisms of tumorigenesis in sporadic cases.

Epigenetic changes, such as LSD1 dysregulation, contribute to acquired resistance in EGFR mutant NSCLCs and reduce the effectiveness of current therapeutics. To address the challenges, we herein reported the structure-based design of new LSD1/EGFR dual inhibitors, of which ZJY-54 represents the shortlisted lead compound with high potency, selectivity, and unique dual modes of action (namely irreversibly binding to EGFR but reversibly binding to LSD1). ZJY-54 effectively inhibited growth in both parent- and TKI-resistant NSCLC cells. In H1975 cells, ZJY-54 induced accumulation of H3K4me2 and H3K9me2, as well as inhibited phosphorylation of EGFR signaling. ZJY-54 showed favorable PK profiles and effectively inhibited tumor growth in the H1975 xenograft model. ZJY-54 represents the best-in-class LSD1/EGFR dual inhibitor and warrants further preclinical development for treating NSCLCs. These findings highlight the therapeutic potential of LSD1/EGFR dual inhibitors in drug-resistant cancers where EGFR and LSD1 were dysregulated.

Immunotherapy of cancer is now an essential pillar of treatment for patients with many individual tumor types. Novel immune targets and technical advances are driving a rapid exploration of new treatment strategies incorporating immune agents in cancer clinical practice. Immunotherapies perturb a complex system of interactions among genomically unstable tumor cells, diverse cells within the tumor microenvironment including the systemic adaptive and innate immune cells. The drive to develop increasingly effective immunotherapy regimens is tempered by the risk of immune-related adverse events. Evidence-based biomarkers that measure the potential for therapeutic response and/or toxicity are critical to guide optimal patient care and contextualize the results of immunotherapy clinical trials. Responding to the lack of guidance on biomarker testing in early-phase immunotherapy clinical trials, we propose a definition and listing of essential biomarkers recommended for inclusion in all such protocols. These recommendations are based on consensus provided by the Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Network (SCION) faculty with input from the SITC Pathology and Biomarker Committees and the Journal for ImmunoTherapy of Cancer readership. A consensus-based selection of essential biomarkers was conducted using a Delphi survey of SCION faculty. Regular updates to these recommendations are planned. The inaugural list of essential biomarkers includes complete blood count with differential to generate a neutrophil-to-lymphocyte ratio or systemic immune-inflammation index, serum lactate dehydrogenase and albumin, programmed death-ligand 1 immunohistochemistry, microsatellite stability assessment, and tumor mutational burden. Inclusion of these biomarkers across early-phase immunotherapy clinical trials will capture variation among trials, provide deeper insight into the novel and established therapies, and support improved patient selection and stratification for later-phase clinical trials.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Advances in tissue-based biomarkers have significantly enhanced diagnostic and therapeutic approaches in NSCLC, enabling precision medicine strategies. This review provides a comprehensive analysis of the molecular pathologist's practical approach to assessing NSCLC biomarkers across various specimen types (liquid biopsy, broncho-alveolar lavage, transbronchial biopsy/endobronchial ultrasound-guided biopsy, and surgical specimen), including challenges such as biological heterogeneity and preanalytical variability. We discuss the role of programmed death ligand 1 (PD-L1) immunohistochemistry in predicting immunotherapy response, the practice of histopathological tumor regression grading after neoadjuvant chemoimmunotherapy, and the application of DNA- and RNA-based techniques for detecting actionable molecular alterations. Finally, we emphasize the critical need for quality management to ensure the reliability and reproducibility of biomarker testing in NSCLC.

Lung cancer remains a challenge within the realm of oncology. Characterized by late-stage diagnosis and resistance to conventional treatments, the currently available therapeutic strategies encompass surgery, radiotherapy, chemotherapy, immunotherapy, and biological therapy; however, overall patient survival remains suboptimal. Nanotechnology has ushered in a new era by offering innovative nanomaterials with the potential to precisely target cancer cells while sparing healthy tissues. It holds the potential to reshape the landscape of cancer management, offering hope for patients and clinicians. The assessment of these nanotechnologies follows a rigorous evaluation process similar to that applied to chemical drugs, which includes considerations of their pharmacokinetics, pharmacodynamics, toxicology, and clinical effectiveness. However, because of the characteristics of nanoparticles, standard toxicological tests require modifications to accommodate their unique characteristics. Effective therapeutic strategies demand a profound understanding of the disease and consideration of clinical outcomes, physicochemical attributes of nanomaterials, nanobiointeractions, nanotoxicity, and regulatory compliance to ensure patient safety. This review explores the promise of nanomedicine in lung cancer treatment by capitalizing on its unique physicochemical properties. We address the multifaceted challenges of lung cancer and its tumor microenvironment and provide an overview of recent developments in nanoplatforms for early diagnosis and treatment that can enhance patient outcomes and overall quality of life.

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is a first-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR mutations, including both sensitizing and T790M resistance mutations. Its real-world efficacy against uncommon EGFR mutations remains under-researched.

The REIWA study, a multicentric, prospective, observational study conducted in Japan from September 2018 to August 2020, enrolled patients with advanced or recurrent EGFR mutation-positive NSCLC receiving osimertinib. Data on clinical outcomes, safety, disease progression, and subsequent treatments were collected for patients with uncommon EGFR mutations.

Of 583 patients receiving osimertinib, 39 (6.7%) had an uncommon EGFR mutation. The present study included 32 of these patients after excluding seven patients with an exon 20 insertion mutation. The overall objective response rate was 53.1% [95% confidence interval (CI): 36.4-69.1], and the disease control rate was 78.1% (95% CI: 61.0-89.3). The median progression-free survival was 9.4 months (95% CI: 5.0-20.0), and the median overall survival (OS) was 21.8 (95% CI: 14.4-NA) months. Notably, patients with an exon21 L861Q mutation had a significantly longer OS than those with an exon18 G719X mutation, the respective values being 37.8 and 9.7 months (hazard ratio: 0.29; 95% CI: 0.10-0.85; P = 0.02). The rate of grade 3 or worse adverse events was 10.3%. Seven out of 32 (21.9%) patients showed progression involving only the central nervous system.

Osimertinib demonstrated efficacy and tolerability in the clinical setting in patients with uncommon EGFR mutation-positive NSCLC.

Health care system-wide outcomes from routine treatment with erlotinib and gefitinib are incompletely understood.

The aim of the study is to describe the effectiveness of erlotinib and gefitinib during the first decade of their routine use for treating advanced epidermal growth factor receptor (EGFR) mutation-positive nonsquamous non-small cell lung cancer in the entire cohort of patients treated in Aotearoa New Zealand.

Patients were identified, and data collated from national pharmaceutical dispensing, cancer registration, and mortality registration electronic databases by deterministic data linkage using National Health Index numbers. Time-to-treatment discontinuation and overall survival were measured from the date of first dispensing of erlotinib or gefitinib and analyzed by Kaplan-Meier curves. Associations of treatment outcomes with baseline factors were evaluated using univariable and multivariable Cox regressions.

Overall, 752 patients were included who started treatment with erlotinib (n=418) or gefitinib (n=334) before October 2020. Median time-to-treatment discontinuation was 11.6 (95% CI 10.8-12.4) months, and median overall survival was 20.1 (95% CI 18.1-21.6) months. Shorter time-to-treatment discontinuation was independently associated with high socioeconomic deprivation (hazard ratio [HR] 1.3, 95% CI 1.1-1.5 compared to the New Zealand Index of Deprivation 1-4 group), EGFR L858R mutations (HR 1.3, 95% CI 1.1-1.6 compared to exon 19 deletion), and distant disease at cancer diagnosis (HR 1.4, 95% CI 1.2-1.7 compared to localized or regional disease). The same factors were independently associated with shorter overall survival. Outcome estimates and predictors remained unchanged in sensitivity analyses.

Outcomes from routine treatment with erlotinib and gefitinib in New Zealand patients with advanced EGFR-mutant nonsquamous non-small cell lung cancer are comparable with those reported in randomized trials and other health care system-wide retrospective cohort studies. Socioeconomic status, EGFR mutation subtype, and disease extent at cancer diagnosis were independent predictors of treatment outcomes in that setting.

Lung cancer treatment has changed in the last twenty years since the discovery of EGFR mutations. In this article, we will review the current state of the art for non-small cell lung cancer (NSCLC) actionable genomic alterations (AGA). AGAs are mostly found in lung adenocarcinomas, a subtype of non-small cell lung cancers. We will focus on the current treatment for EGFR mutations, ALK fusions, ROS1 fusions, BRAF V600E mutations, MET exon 14-skipping mutations, RET fusions, KRAS G12C mutations, ERBB2 mutations (also called HER2 mutations), and NTRK fusions. We will also touch on the key toxicities associated with these medications. Treatments are mostly available for the metastatic stage, but we will also discuss adjuvant therapy for EGFR mutations and ALK fusions, as well as stage III post-chemoradiotherapy treatment for EGFR lung cancer.

Covalent protein targeting represents a powerful tool for protein characterization, identification, and activity modulation. The safety of covalent therapeutics was questioned for many years due to the possibility of off-target binding and subsequent potential toxicity. Researchers have recently, however, demonstrated many covalent binders as safe, potent, and long-acting therapeutics. Moreover, they have achieved selective targeting among proteins with high structural similarities, overcome mutation-induced resistance, and obtained higher potency compared to non-covalent binders. In this review, we highlight the different classes of binding sites on a target protein that could be addressed by a covalent binder. Upon folding, proteins generate various concavities available for covalent modifications. Selective targeting to a specific site is driven by differences in the geometry and physicochemical properties of the binding pocket residues as well as the geometry and reactivity of the covalent modifier "warhead". According to the warhead reactivity and the nature of the binding region, covalent binders can alter or lock a targeted protein conformation and inhibit or enhance its activity. We survey these various modification sites using case studies of recently discovered covalent binders, bringing to the fore the versatile application of covalent protein binders with respect to drug discovery approaches.

EGFR and ALK are key driver mutations in non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors are recommended as the first-line treatment for advanced NSCLC with driving oncogenes because they have fewer side effects and provide better disease control than chemotherapy. The present retrospective analysis aimed to investigate how altered driver genes impact cancer outcomes and clinical presentation. A total of 628 patients with advanced-stage NSCLC and documented EGFR and ALK mutations were enrolled at Changhua Christian Hospital in Taiwan between August 2011 and January 2021. EGFR mutations were identified by PCR. ALK rearrangements were identified by immunostaining. Patients without EGFR or ALK mutations were labeled as wild-type (WT). EGFR mutation was detected in 446 (71.02%) patients, ALK rearrangement in 36 (5.73%) patients and WT in 146 (23.25%) patients. EGFR mutations resulted in higher frequency of lung, brain and multiple extrapulmonary metastases than ALK rearrangement. The ALK group exhibited the longest median overall survival (OS), followed by EGFR and WT groups (ALK: 51.60±13.32, EGFR: 24.03±1.22 and WT: 19.63±2.43 months, respectively; P=0.011). In patients with brain metastases, ALK group had a longer median OS than the EGFR group. Because there were few recruited patients with ALK rearrangement, the results were not significant. According to the results of Cox regression model analysis, driver mutations with EGFR and ALK, lower smoking pack-years, younger age, better performance status, no pleural metastasis and fewer extrapulmonary metastases were key prognostic factors. In conclusion, diverse clinical outcomes are driven by different driver mutations. EGFR mutation leads to more extrapulmonary metastases. Median OS was superior in ALK-rearranged NSCLC than EGFR-mutated NSCLC regardless of brain metastases.

The treatment landscape for people diagnosed with EGFR-mutated (EGFR-m) NSCLC has rapidly evolved, yet there remains limited self-reported information about the lived experience. In this paper, we describe the clinical characteristics and treatment experiences of people living with EGFR-m lung cancer from Project PRIORITY, a patient-driven study.

An online survey was distributed among the EGFR Resisters community between April 2019 and January 2020. The survey captured participants' demographics and lung cancer risk factors, diagnostic and treatment pathways, and prevalence of side effects. Descriptive statistics were used and included subgroups based on residency and cancer stage.

Of the 425 participants, most were female (67%), under 60 years old (53%), and resided in the United States (74%). The most frequently reported symptom at diagnosis was cough (54%), though 18% reported no symptoms. In addition, 89% reported receiving at least one tyrosine kinase inhibitor (TKI); osimertinib was the most prescribed first-line TKI for stage IV participants diagnosed after 2017. Participants residing in the United States were more likely to have access to advanced diagnostic (next-generating sequencing) and newer treatments such as osimertinib. Just under half of the sample (47%) had experienced progressive disease and were no longer on first-line treatment.

The TKI era has been practice changing; however, little is understood from the perspective of people living with EGFR-m NSCLC. This paper is the first to explore this and found it is possible to have people self-report complex health information about their lung cancer. In addition, although most participants were diagnosed after osimertinib became guideline-recommended treatment, disparities in treatment were identified.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC) patients, which remarkably improve the clinical outcomes. However, drug resistance has greatly impaired the efficacy of EGFR-TKIs and contributes to cancer treatment failure. DUSP1, a negative regulator of MAPK signaling pathway, was discovered to mediate drug resistance in multiple types of cancers. Our study aimed to explore the role of DUSP1 in NSCLC cell resistance to osimertinib, a third-generation EGFR-TKI. Human NSCLC cell lines PC-9 and HCC827 were exposed to increasing concentrations of osimertinib for over 6 months to generate osimertinib resistant cells (PC-9-OR and HCC827-OR). The viabilities of osimertinib-resistant and parental sensitive NSCLC cells in response to osimertinib stimulation were detected by MTS assay and the IC50 values for osimertinib were obtained. The differentially expressed genes in osimertinib-resistant and sensitive NSCLC cells were identified by analyzing the GEO dataset GSE106765 using bioinformatic tools. DUSP1 expression was knocked down by using the short hairpin RNAs (shRNAs). Then, the effects of DUSP1 silencing on osimertinib-resistant and sensitive NSCLC cell resistance to osimertinib, viability, proliferation and apoptosis were assessed through loss-of-function experiments. The expression of key molecules (JNK, ERK, and p38 MAPK) in the MAPK signaling pathway was detected through western blotting analysis. DUSP1 was overexpressed in osimertinib-resistant NSCLC cells versus parental sensitive cells. DUSP1 silencing attenuated the resistance of NSCLC cells to osimertinib. DUSP1 silencing markedly inhibited osimertinib-resistant and sensitive NSCLC cell proliferation but enhanced cell apoptosis. Mechanically, DUSP1 knockdown increased phosphorylated-JNK, ERK, and p38 MAPK levels in NSCLC cells. Treatment with SB203580, the p38 MAPK inhibitor, reversed the effects of DUSP1 silencing on osimertinib-resistant NSCLC cell resistance to osimertinib, cell proliferation and apoptosis. DUSP1 downregulation restores the sensitivity of NSCLC cells to osimertinib via activating the MAPK signaling pathway.

The integration of genomics into personalized medicine has the potential to transform healthcare by customizing treatments according to individual genetic profiles. This paper examines the diverse applications of genomics, including the identification of disease susceptibility, improvement of diagnostic methods, optimization of drug therapies, and monitoring of treatment responses. It also explores the expanding global market for genetic testing and the increasing implementation of whole-genome sequencing in clinical practice, with a focus on pilot programs that are advancing comprehensive genomic analysis. Despite challenges such as high costs, data interpretation complexities, and ethical concerns, significant efforts are being made to address these issues. Additionally, the creation of biobanks as vital resources for preserving high-quality biosamples and supporting research highlights the critical need for infrastructure development in genomics. By fostering interdisciplinary collaboration and establishing robust ethical and regulatory frameworks, personalized medicine can ensure equitable access to tailored therapies and enhance health outcomes for everyone. This abstract provides an overview of the transformative potential of genomics and personalized medicine in ushering in a new era of precision healthcare.

The expanding armamentarium of targeted therapies has revolutionized treatment for metastatic oncogene-addicted lung cancers. For multiple subsets, such as those harboring EGFR mutations and fusions in ALK or ROS1, successive generation of increasingly potent, selective, and brain-penetrating targeted therapies have shifted the treatment paradigm towards preferential first-line use of next-generation drugs. This evolution in clinical practice provides a lens through which to review the lessons learned from drug development in oncogene-addicted lung cancers, guided by translational insights into tumor biology and mechanisms of therapeutic resistance. For oncogenic drivers that are less sensitive to single-agent targeted therapies, rationally designed combination strategies will be needed to enable first-line use of targeted agents.

In hereditary papillary renal cell carcinoma (HPRCC), the hepatocyte growth factor receptor (MET) receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET activation. This contrasts with MET mutations identified in non-small cell lung cancer (NSCLC), which lead to exon 14 skipping and deletion of a regulatory domain: in this latter case, the mutated receptor still requires ligand stimulation. Sequencing of MET in samples from 158 HPRCC and 2808 NSCLC patients revealed ten uncharacterized mutations. Four of these, all found in HPRCC and leading to amino acid substitutions in the N-lobe of the MET kinase, proved able to induce cell transformation, which was further enhanced by hepatocyte growth factor (HGF) stimulation: His1086Leu, Ile1102Thr, Leu1130Ser and Cis1125Gly. Similar to the variant resulting in MET exon 14 skipping, the two N-lobe MET variants His1086Leu and Ile1102Thr were found to require stimulation by HGF in order to strongly activate downstream signaling pathways and epithelial cell motility. The Ile1102Thr mutation also displayed transforming potential, promoting tumor growth in a xenograft model. In addition, the N-lobe-mutated MET variants were found to trigger a common HGF-stimulation-dependent transcriptional program, consistent with an observed increase in cell motility and invasion. Altogether, this functional characterization revealed that N-lobe variants still require ligand stimulation, in contrast to other RTK variants. This suggests that HGF expression in the tumor microenvironment is important for tumor growth. The sensitivity of these variants to MET inhibitors opens the way for use of targeted therapies for patients harboring the corresponding mutations.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) have garnered substantial clinical success in treating nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the inevitable emergence of drug resistance, frequently attributed to activation, mutation, or deletion of multiple signaling pathways, poses a significant challenge. Notably, the loss of PTEN protein expression has emerged as a pivotal mechanism fostering resistance in EGFR mutant lung cancers. Consequently, strategies aimed at upregulating PTEN expression hold great promise for restoring drug sensitivity. Leveraging the versatility, precision, and efficacy of nuclease-deactivated Cas9 (dCas9) as a transcriptional activator, we designed a CRISPR-dCas9 system to stimulate PTEN expression. To further enhance target specificity and drug delivery efficiency, we innovatively harnessed the tumor cell membrane (CCM) as a homologous targeting surface coating for our vector, thereby creating a targeted activation nanoplatform. Comprehensive in vitro and in vivo evaluations demonstrated that the synergistic interplay between gefitinib and the CRISPR-dCas9 system significantly enhanced drug sensitivity. The finding underscores the potential of our approach in addressing the issue of lung cancer resistance, offering a promising avenue for personalized and effective cancer therapies.

In hereditary papillary renal cell carcinoma (HPRCC), the hepatocyte growth factor receptor (MET) receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET activation. This contrasts with MET mutations identified in non-small-cell lung cancer (NSCLC), which lead to exon 14 skipping and deletion of a regulatory domain: In this latter case, the mutated receptor still requires ligand stimulation. Sequencing of MET in samples from 158 HPRCC and 2808 NSCLC patients revealed 10 uncharacterized mutations. Four of these, all found in HPRCC and leading to amino acid substitutions in the N-lobe of the MET kinase, proved able to induce cell transformation, which was further enhanced by hepatocyte growth factor (HGF) stimulation: His1086Leu, Ile1102Thr, Leu1130Ser, and Cis1125Gly. Similar to the variant resulting in MET exon 14 skipping, the two N-lobe MET variants His1086Leu and Ile1102Thr were found to require stimulation by HGF in order to strongly activate downstream signaling pathways and epithelial cell motility. The Ile1102Thr mutation also displayed transforming potential, promoting tumor growth in a xenograft model. In addition, the N-lobe-mutated MET variants were found to trigger a common HGF-stimulation-dependent transcriptional program, consistent with an observed increase in cell motility and invasion. Altogether, this functional characterization revealed that N-lobe variants still require ligand stimulation, in contrast to other RTK variants. This suggests that HGF expression in the tumor microenvironment is important for tumor growth. The sensitivity of these variants to MET inhibitors opens the way for use of targeted therapies for patients harboring the corresponding mutations.

Mutations in human receptor tyrosine kinase epidermal growth factor receptor-2 (HER2) are rare. This study aimed to investigate the clinical characteristics and computed tomography (CT) texture features of lung adenocarcinoma (LUAD) patients with HER2 mutation.

This study included 933 LUAD patients from January 2018 to December 2023 and classified their CT textures accordingly.

The data indicated that the incidence of HER2 mutation was higher in younger LUAD patients than in elder patients [7.5% (31/413) vs. 1.5% (8/520), p < 0.0001] and was associated with never-smokers [0% (0/78) vs. 4.6% (39/855), p = 0.03]. In this study, the tumors were categorized based on their diameter into T1a and ≥ T1b. The data revealed that HER2 mutation was more frequent in T1a than in ≥ T1b [11.0% (23/210) vs. 2.2% (16/723), p < 0.0001]. Furthermore, non-pSD was more common than pSD in LUAD with HER2 mutation than in LUAD with HER2 wild type [82.1% (31/39) vs.17.9% (7/39), p = 0.01]. Moreover, the size of pGGO (0.94 ± 0.29 cm vs. 1.24 ± 0.39 cm, p = 0.0009), mGGO (0.86 ± 0.39 cm vs. 1.5 ± 0.77 cm, p < 0.0001) and pSD (1.75 ± 0.81 cm vs. 2.5 ± 1.4 cm, p < 0.05) in LUAD patients with HER2 mutation was smaller than those with HER2 wild type patients. In addition, when LUADs with HER2 wild type transformed from pGGO to mGGO, their sizes increased significantly (1.50 ± 0.77 cm vs. 1.24 ± 0.39 cm). It was also observed that the incidence of LUAD with HER2 mutation of ≤ 1 cm was significantly more than that of > 1 cm comparing to that in LUAD with HER2 wild type [14.8% (12/81) vs. 1.7% (3/173), p < 0.0001].

This study indicated that the incidence of HER2 mutation was higher in younger and never-smoking LUAD patients. Furthermore, the growth of LUAD with HER2 mutation was slower than that of those with HER2 wild type. Moreover, most LUAD with HER2 mutation changed into pSD after > 1 cm.

Over the past decades, significant progress has been made in the understanding of non-small cell lung cancer (NSCLC) biology and tumor progression mechanisms, resulting in the development of novel strategies for early detection and wide-ranging care approaches. Since their introduction, over 20 years ago, targeted therapies with tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for NSCLC. Nowadays, targeted therapies remain the gold standard for many patients, but still they suffer from many adverse effects, including unexpected toxicity and intrinsic acquired resistance mutations, which lead to relapse. The adoption of immune checkpoint inhibitors (ICIs) in 2015, has offered exceptional survival benefits for patients without targetable alterations. Despite this notable progress, challenges remain, as not all patients respond favorably to ICIs, and resistance to therapy can develop over time. A crucial factor influencing clinical response to immunotherapy is the tumor microenvironment (TME). The TME is pivotal in orchestrating the interactions between neoplastic cells and the immune system, influencing tumor growth and treatment outcomes. In this review, we discuss how the understanding of this intricate relationship is crucial for the success of immunotherapy and survey the current state of immunotherapy intervention, with a focus on forthcoming and promising chimeric antigen receptor (CAR) T cell therapies in NSCLC. The TME sets major obstacles for CAR-T therapies, creating conditions that suppress the immune response, inducing T cell exhaustion. To enhance treatment efficacy, specific efforts associated with CAR-T cell therapy in NSCLC, should definitely focus TME-related immunosuppression and antigen escape mechanisms, by combining CAR-T cells with immune checkpoint blockades.

The combination of PD-1/PD-L1 inhibitor with CTLA-4 inhibitor for advanced non-small cell lung cancer(NSCLC) is presently a significant area of research, however its clinical application remains contentious. This meta-analysis aimed to assess the efficacy and safety of first-line PD-1/PD-L1 inhibitor in combination with CTLA-4 inhibitor (CP) in the treatment of patients with advanced NSCLC.

A systemic search was conducted in four databases (PubMed, Cochrane library, Embase, and Web of Science) from their establishment until January 17, 2024, for randomized controlled trials that investigated the use of the first-line PD-1/PD-L1 inhibitor plus CTLA-4 inhibitor in patients with advanced NSCLC. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were subjected to meta-analyses.

Totally 7 eligible randomized controlled trials including 4682 people were included. Two comparative analyses were performed: CP versus chemotherapy, CP versus PD-1/PD-L1 inhibitor (P). Compared with the chemotherapy group, CP improved OS (HR: 0.84, 95% CI: 0.75-0.94, p<0.05) but not PFS (HR: 0.94, 95%CI: 0.73-1.20, p = 0.63) or ORR (OR: 1.16, 95% CI: 0.79-1.71, p = 0.45). In terms of toxicity, CP had slightly fewer any AEs compared to chemotherapy (RR: 0.94, 95% CI: 0.91-0.97; p<0.05). Compared to the P group, there was no significant difference in OS (MD: -0,25, 95% CI: -2.47-1.98, p = 0.83), PFS (MD: -0.91, 95% CI: -3.19-1.36, p = 0.43), and ORR (OR:1.05, 95% CI. 0.80-1.36, p = 0.73). Subgroup analysis revealed that CP provided superior OS compared with P in patients with PD-L1 expression < 1%.

CP was a feasible and safe first-line therapy for patients with advanced NSCLC. Specifically, CP may function as a therapeutic alternative for individuals with low or negative PD-L1 expression, resulting in enhanced long-term outcomes compared to chemotherapy or P. Further randomized controlled trials with prolonged follow-up periods are necessary to validate these results, particularly focusing on efficacy in patients with differing PD-L1 expression levels, to improve the stratified implementation of immunotherapy.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024621116, identifier CRD42024621116.

Non-small cell lung carcinoma (NSCLC) comprises the majority of lung cancer cases, characterized by a complex interplay of genetic alterations, environmental factors, and molecular pathways contributing to its pathogenesis. This article highlights the multifaceted pathogenesis of NSCLC and discusses screening and integrated strategies for current treatment options. NSCLC is an evolving field with various aspects including the underlying molecular alterations, oncogenic driver mutations, and immune microenvironment interactions that influence tumor progression and response to therapy. Surgical treatment remains the most applicable curative option, especially in the early stages of the disease, adjuvant chemotherapy may add benefits to previously resected patients. Combined Radio-chemotherapy can also be used for palliative purposes. There are various future perspectives and advancing horizons in NSCLC management, encompassing novel therapeutic modalities and their applications, such as CAR-T cell therapy, antibody-drug conjugates, and gene therapies. On the other hand, it's crucial to highlight the efficacy of innovative modalities of Immunotherapy and immune checkpoint inhibitors that are nowadays widely used in treatment of NSCLC. Moreover, the latest advancements in molecular profiling techniques and the development of targeted therapies designed for specific molecular alterations in NSCLC play a significant role in its treatment. In conclusion, personalized approaches are a cornerstone of successful treatment, and they are based on a patient's unique molecular profile, tumor characteristics, and host factors. Entitling the concept of individualized treatment strategies requires proper patient selection, taking into consideration mechanisms of resistance, and investigating potential combination therapies, to achieve the optimal impact on long-term survival.

Determining mutations in the kinase domain of the epidermal growth factor receptor (EGFR) is critical for the effectiveness of EGFR tyrosine kinase inhibitors (TKIs) in lung cancer. Yet, DNA-based sequencing analysis of tumor samples is time-consuming and only provides gene mutation information on EGFR, making it challenging to design effective EGFR-TKI therapeutic strategies. Here, we present a new image-based method involving the rational design of a quenched probe based on EGFR-TKI to identify mutant proteins, which permits specific and "no-wash" real-time imaging of EGFR in living cells only upon covalent targeting of the EGFR kinase. We also show that the probe enables distinguishing EGFR mutant tumor-bearing mice from wild-type tumor-bearing mice via fluorescence-intensity-based imaging with high signal contrast. More interestingly, the image-based phenotypic approach can be used to predict EGFR mutations in tumors from lung cancer patients with an accuracy of 94%. Notably, when immunohistochemistry analysis is integrated, an improved accuracy of 98% is achieved. These data delineate a drug-based phenotypic imaging approach for in-biopsy visualization and define functional groups of EGFR mutants that can effectively guide EGFR-TKI therapeutic decision-making besides gene mutation analysis.

Non-small cell lung cancer (NSCLC) patients with pleural dissemination are generally contraindicated for surgery. This study aimed to investigate the survival benefits of primary tumor resection for NSCLC patients with unexpectedly detected pleural disseminated nodules during thoracotomy in the era of targeted therapy.

Of the 4984 patients with NSCLC who underwent surgery without induction therapy between 2000 and 2021, we retrospectively evaluated 90 (1.8%) patients with unexpectedly detected pleural disseminated nodule. Survival analyses were performed with Kaplan-Meier methods and Cox proportional hazards regression.

Among the evaluated patients, 58 were male, the median age was 67, and 77 (86%) were diagnosed with adenocarcinoma. Exploratory thoracotomy was performed in 21 (23%), and primary tumor resection was performed in 69 (77%) patients, including pneumonectomy in four, lobectomy in 39, and sublobar resection in 26. Epidermal growth factor receptor gene mutation and anaplastic lymphoma kinase rearrangement were detected in 33 (37%) and 4 (4%) cases, respectively. Among them, 31 patients received targeted therapy. The overall survival (OS) was not significantly different between patients with primary tumor resection and exploratory thoracotomy (5-year OS rate: 30.2% vs. 27.8%, p = 0.81). Multivariable analysis revealed that sex (p = 0.02) and targeted therapy (p < 0.01) were independent prognostic factors for OS. Survival outcomes in patients who received targeted therapy were significantly better regardless of primary tumor resection.

Primary tumor resection might not affect the survival in NSCLC patients with unexpectedly detected pleural disseminated nodules in the era of targeted therapy.

The epidermal growth factor receptor (EGFR) has been extensively studied for its critical role in the development and progression of various malignancies. In this comprehensive pan-cancer analysis, we investigated the potential of EGFR as a biomarker across multiple tumor types; a comprehensive analysis of EGFR gene mutation and copy number variation was conducted using cBioPortal and other tools. Utilizing multi-omics datasets from The Cancer Genome Atlas (TCGA), we analyzed EGFR's expression patterns, prognostic implications, genetic mutations, and molecular interactions in different cancers. Our findings revealed frequent dysregulation of EGFR in several tumor types, including lung cancers and glioblastoma multiforme. High EGFR expression was consistently associated with poor clinical outcomes, such as reduced overall survival, disease-free survival, and progression-free survival. Genetic alteration analysis indicated a high frequency of EGFR mutations and copy number variations, particularly in glioblastoma multiforme. Additionally, our study suggests a complex relationship between EGFR expression and cancer-associated fibroblast infiltration, which may contribute to an immunosuppressive tumor microenvironment. These findings underscore the clinical relevance of EGFR as a prognostic biomarker and therapeutic target, emphasizing the need for further research and the development of targeted therapies to enhance patient outcomes in cancers with EGFR alterations. The co-expression network of EGFR with genes and proteins involved in cell cycle regulation and mitotic control provided insights into the molecular mechanisms of oncogenesis.

The discovery of the association between EGFR mutations and the efficacy of EGFR tyrosine-kinase inhibitors (TKIs) has revolutionized the treatment paradigm for patients with non-small-cell lung cancer (NSCLC). Currently, third-generation EGFR TKIs, which are often characterized by potent central nervous system penetrance, are the standard-of-care first-line treatment for advanced-stage EGFR-mutant NSCLC. Rational combinations of third-generation EGFR TKIs with anti-angiogenic drugs, chemotherapy, the EGFR-MET bispecific antibody amivantamab or local tumour ablation are being investigated as strategies to delay drug resistance and increase clinical benefit. Furthermore, EGFR TKIs are being evaluated in patients with early stage or locally advanced EGFR-mutant NSCLC, with the ambitious aim of achieving cancer cure. Despite the inevitable challenge of acquired resistance, emerging treatments such as new TKIs, antibody-drug conjugates, new immunotherapeutic approaches and targeted protein degraders have shown considerable promise in patients with progression of EGFR-mutant NSCLC on or after treatment with EGFR TKIs. In this Review, we describe the current first-line treatment options for EGFR-mutant NSCLC, provide an overview of the mechanisms of acquired resistance to third-generation EGFR TKIs and explore novel promising treatment strategies. We also highlight potential avenues for future research that are aimed at improving the survival outcomes of patients with this disease.

Introduction Epidermal growth factor receptor (EGFR) mutation analysis has become an important part of the initial workup of non-squamous non-small cell lung cancer (NS-NSCLC) patients as it is now recognized both as a prognostic and predictive marker for therapy with EGFR tyrosine kinase inhibitors (TKIs). The data on the prevalence of mutation and its clinical profile in bronchogenic adenocarcinoma are vastly available from Eastern Asian and European countries. The frequency of EGFR mutations in India however remains sparsely explored. Activating EGFR mutations in the tyrosine kinase region have been shown to underlie response to these inhibitors. However, the frequency of EGFR mutations and their clinical response in most other ethnic populations, including India, remains to be explored. In addition to providing information on the stage of the disease and the Eastern Cooperative Oncology Group (ECOG) performance scale at presentation, this is one of the rare studies from the subcontinent where EGFR mutation was performed in a single laboratory using a standardized procedure. The aims and objectives of the study are to estimate the prevalence of EGFR gene mutation in adenocarcinoma of the lung and to assess the clinical profile that correlates with EGFR gene status. Material and methods This single-center-based cross-sectional study was conducted at R.L. Jalappa Hospital, Kolar, India, over eight months (October 2023 to June 2024). The study included patients diagnosed with NSCLC adenocarcinoma whose participation was secured through informed consent. These tissues had been tested for EGFR mutational status. EGFR mutation analysis will be done on extracted DNA with real-time polymerase chain reaction to estimate the prevalence of EGFR mutation in adenocarcinoma of the lung. All data were entered in a Microsoft Excel sheet (Redmond, WA, USA) and statistical analysis will be performed using SPSS statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY). Categorical data were represented in the form of frequencies and proportions. To check the association between qualitative data, Chi-square was applied with a level of significance defined as a p-value < 0.05. Continuous data was represented as mean and standard deviation. Results Of the 61 patients included in the study, the mean age of prevalence of EGFR mutation in adenocarcinoma was 58.13 years, with a prevalence rate of 31.1%. EGFR mutation was positive in 11 (42.3%) females and eight (22.8%) males. The prevalence of exon 19 deletion was the most common and was higher in females (seven (26.4%)) compared to males (eight (22.9%)). However, among those with an ECOG score of 3, one (2.3%) had EXON 18 G719S G719A G719C, and 14 (31.8%) had EXON 19 deletion. There was a significant difference (p-value<0.008) in the type of mutations concerning the ECOG performance scale. Conclusion The prevalence of activating EGFR mutations and their clinical correlations in our study are comparable with those previously published and Indian patients with EGFR mutations. In line with data already available from previously published studies, EGFR mutation is also a common finding in patients with lung adenocarcinoma, especially among women, and the exon 19 deletion is the most common variation. Incorporating EGFR mutation testing into early diagnostic protocols remains crucial for optimizing treatment strategies and improving patient outcomes.

Non-small cell lung cancers (NSCLC) harboring common mutations in EGFR and KRAS characteristically respond transiently to targeted therapies against those mutations, but invariably, tumors recur and progress. Resistance often emerges through mutations in the therapeutic target or activation of alternative signaling pathways. Mechanisms of acute tumor cell resistance to initial EGFR (EGFRi) or KRASG12C (G12Ci) pathway inhibition remain poorly understood. Our study reveals that acute response to EGFR/RAS/RAF-pathway inhibition is spatial and culture context specific. In vivo, EGFR mutant tumor xenografts shrink by > 90% following acute EGFRi therapy, and residual tumor cells are associated with dense stroma and have increased nuclear YAP. Interestingly, in vitro EGFRi induced cell cycle arrest in NSCLC cells grown in monolayer, while 3D spheroids preferentially die upon inhibitor treatment. We find differential YAP nuclear localization and activity, driven by the distinct culture conditions, as a common resistance mechanism for selective EGFR/KRAS/BRAF pathway therapies. Forced expression of the YAPS127A mutant partially protects cells from EGFR-mediated cell death in spheroid culture. These studies identify YAP activation in monolayer culture as a non-genetic mechanism of acute EGFR/KRAS/BRAF therapy resistance, highlighting that monolayer vs spheroid cell culture systems can model distinct stages of patient cancer progression.

Background/Objectives: The accurate detection of EGFR mutations, particularly the rare S768I variant, is crucial for guiding treatment decisions in non-small cell lung cancer (NSCLC) patients. This study investigated the incidence of false positives in S768I mutation detection using the IdyllaTM qPCR system and compared results with next-generation sequencing (NGS). Methods: A prospective observational study was conducted at the Dr. Negrín University Hospital between July 2023 and July 2024. Six NSCLC patient samples with S768I variant detection by IdyllaTM were analyzed from all NSCLC cases tested during the study period. Initial testing was performed on tissue samples (Idylla1), followed by replicate analysis using extracted DNA (Idylla2). Results were compared with NGS as the reference method. Statistical analysis included the calculation of sensitivity, specificity, accuracy, and Kappa concordance index. Results: Initial Idylla testing showed an 80% false positive rate, with only one of five positive results confirmed by NGS. The first analysis demonstrated high sensitivity (100%) but low specificity (20%), with an accuracy of 0.333 and poor concordance with NGS (Kappa = 0.077). Repeat testing using extracted DNA showed improved performance, with increased accuracy (0.833) and better agreement with NGS (Kappa = 0.571). Analysis of amplification curves revealed that false positives typically showed normalized fluorescence values below 12 points, with no clear correlation between false positives and factors such as sample quantity or tumor content. Conclusions: While the IdyllaTM system shows high sensitivity for S768I detection, its initial specificity is problematic, leading to frequent false positives. These findings emphasize the importance of confirming positive S768I results through alternative methods like NGS, particularly when these results could influence therapeutic decisions. Results suggest the need to refine the system's interpretation algorithms to improve specificity.

Next-generation sequencing has revolutionized genome science over the last two decades. Indeed, the wealth of sequence information on our genome has deepened our understanding on cancer. Cancer is a genetic disease caused by genetic or epigenetic alternations that affect the expression of genes that control cell functions, particularly cell growth and division. Utilization of next-generation sequencing in cancer gene panels has enabled the identification of actionable gene alterations in cancer patients to guide personalized precision medicine.

The aim is to provide information that can identify actionable gene alterations, enabling personalized precision medicine for cancer patients.

Equipped with next-generation sequencing techniques, international collaboration programs on cancer genomics have identified numerous mutations, gene fusions, microsatellite variations, copy number variations, and epigenetics changes that promote the transformation of normal cells into tumors. Cancer classification has traditionally been based on cell type or tissue-of-origin and the morphological characteristics of the cancer. However, interactive genomic analyses have currently reclassified cancers based on systemic molecular-based taxonomy. Although all cancer-causing genes and mechanisms have yet to be completely understood or identified, personalized or precision medicine is now currently possible for some forms of cancer. Unlike the "one-size-fits-all" approach of traditional medicine, precision medicine allows for customized or personalized treatment based on genomic information.

Despite the availability of numerous cancer gene panels, technological innovation in genomics and expansion of knowledge on the cancer genome will allow precision oncology to manage even more types of cancers.

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used in the treatment of EGFR mutation-positive advanced non-small cell lung cancer. Osimertinib-induced cutaneous vasculitis is a rare skin adverse reaction. We present a case study of a 49-year-old female who developed palpable purpura on her lower extremities on the 11th day of osimertinib treatment. Systemic involvement was not observed in the test results. The multidisciplinary team considered the clinical presentation of purpura as a potential case of cutaneous vasculitis. Osimertinib was immediately discontinued, and intravenous methylprednisolone along with oral cetirizine treatment was initiated. After 8 days since discontinuation of osimertinib, the patient's skin purpura completely subsided. Subsequently, she was switched to almonertinib for treatment. We also conducted a literature review cutaneous vasculitis induced by osimertinib and other EGFR-TKIs. We hope to provide some safety alert information for clinical practice and recommend enhanced monitoring during the medication process.

Furmonertinib, a third generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), is used for non-small cell lung cancer (NSCLC). Rivaroxaban and apixaban are direct oral anticoagulants (DOACs) used for venous thromboembolism (VTE), which is a frequent comorbid with NSCLC. They are substrates of CYP3A4, P-gp and BCRP, whereas furmonertinib is an inhibitor of P-gp and BCRP. This study aimed to disclose the extent of effect of furmonertinib on the pharmacokinetics of rivaroxaban or apixaban. Rats were divided into four groups (n = 6) that received rivaroxaban (group 1), furmonertinib and rivaroxaban (group 2), apixaban (group 3), furmonertinib and apixaban (group 4). The concentrations of drugs were measured by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Furmonertinib increased the Cmax and AUC0-t of rivaroxaban by 1.66 and 2.07-fold, whereas decreased the CLz/F by 1.70-fold and Vz/F 1.27-fold. Furthermore, furmonertinib caused similar changes in apixaban pharmacokinetics. The pharmacokinetic results suggest that it is essential to alert the effect of furmonertinib on the pharmacokinetics of rivaroxaban or apixaban in clinical practice.

The epidermal growth factor receptor (EGFR) regulates gene expression through two primary mechanisms: as a growth factor in the nucleus, where it translocates upon binding its ligand, or via its intrinsic tyrosine kinase activity in the cytosol, where it modulates key signaling pathways such as RAS/MYC, PI3K, PLCγ, and STAT3. During tumorigenesis, these pathways become deregulated, leading to uncontrolled proliferation, enhanced migratory and metastatic capabilities, evasion of programmed cell death, and resistance to chemotherapy or radiotherapy. The RAS and MYC oncogenes are pivotal in tumorigenesis, driving processes such as resistance to apoptosis, replicative immortality, cellular invasion and metastasis, and metabolic reprogramming. These oncogenes are subject to regulation by a range of epigenetic and post-transcriptional modifications. This review focuses on the deregulation of EGFR, RAS, and MYC expression caused by (epi)genetic alterations and post-translational modifications. It also explores the therapeutic potential of targeting these regulatory proteins, emphasizing the importance of phenotyping neoplastic tissues to inform the treatment of cancer.