Despite decreasing trends in incidence, colorectal cancer (CRC) is still a major contributor to malignancy-related morbidities and mortalities. Groundbreaking advances in immunotherapies and targeted therapies benefit a subset of CRC patients, with sub-optimal outcomes. Hence, there is an unmet need to design and manufacture novel therapies, especially for advanced/metastatic disease. KRAS, the most highly mutated proto-oncogene across human malignancies, particularly in pancreatic adenocarcinoma, non-small cell lung cancer, and CRC, is an on-off switch and governs several fundamental cell signaling cascades. KRAS mutations not only propel the progression and metastasis of CRC but also critically modulate responses to targeted therapies.

We discuss the impacts of KRAS mutations on the CRC's tumor microenvironment and describe novel strategies for targeting KRAS and its associated signaling cascades and mechanisms of drug resistance.

Drug development against KRAS mutations has been challenging, mainly due to structural properties (offering no appropriate binding site for small molecules), critical functions of the wild-type KRAS in non-cancerous cells, and the complex network of its downstream effector pathways (allowing malignant cells to develop resistance). Pre-clinical and early clinical data offer promises for combining KRAS inhibitors with immunotherapies and targeted therapies.

Alpelisib, an oral α-specific phosphoinositide 3-kinase (PI3K) inhibitor, has been shown to be safe and effective for some patients with gain-of-function mutation in the PIK3CA oncogene. Alpelisib has received US FDA accelerated approval as Vijoice® film-coated tablets to treat severe PIK3CA-Related Overgrowth Spectrum (PROS). PROS typically displays clinical manifestations in the first year of patient life. Therefore, oral granules were developed as an age-appropriate pediatric dosage form. Bioequivalence between alpelisib granules and tablet and the effect of food on granules pharmacokinetics were assessed in a single-center, randomized, three-treatment, six-sequence, three-period, crossover study among 60 healthy adults. Participants were randomly assigned to receive a single 50-mg alpelisib dose as: (i) tablet following a meal, (ii) granules following a meal, and (iii) granules while fasting. Statistical analysis of non-compartmental pharmacokinetic parameters demonstrated bioequivalence between the 50-mg alpelisib granules and tablet forms when administered with food: estimated geometric mean ratios (90% confidence interval) for granules-versus-tablet area under the curve (AUC) from time zero to infinity (AUCinf), to the last measurable concentration (AUClast) and maximum observed concentration (Cmax) were 0.984 (0.952, 1.02), 0.980 (0.946, 1.02), and 0.947 (0.891, 1.01), respectively. No clinically relevant food effect on 50-mg alpelisib granules pharmacokinetics was observed. These results were accurately predicted using physiologically based biopharmaceutical modeling. Alpelisib granules provide a bioequivalent alternative to tablets for patients prescribed a 50-mg dose and have difficulty swallowing tablets, an important consideration for convenience and compliance of this standard-of-care chronic therapy for patients with PROS. This study was registered in ClinicalTrials.gov on January 4, 2022 (NCT05195892).

Cytosolic arginine sensor for mTORC1 Subunit 1 (CASTOR1) functions as a key regulator of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Despite its frequent dysregulation in cancers via mechanisms such as KSHV microRNA-mediated inhibition or AKT-driven phosphorylation and degradation, the impact of CASTOR1 loss on tumor initiation and progression remains poorly understood. Here, we identify CASTOR1 as a critical tumor suppressor in non-small cell lung cancer (NSCLC) by demonstrating that its genetic ablation amplifies tumorigenesis in a KRAS -driven genetically engineered mouse model (GEMM;LSL- KRAS G12D ). CASTOR1 deficiency markedly enhances lung tumor incidence, accelerates tumor progression, and increases proliferative indices in KRAS G12D -driven tumors ( KRAS G12D ; C1 KO ) compared to CASTOR1 wild type (WT) tumors ( KRAS G12D ; C1 WT ). Advanced-stage tumors exhibit elevated phosphorylated CASTOR1 (pCASTOR1) and reduced total CASTOR1 levels, suggesting active degradation during tumorigenesis. Mechanistically, CASTOR1 loss amplifies mTORC1 signaling, as evidenced by heightened phosphorylation of downstream effectors 4EBP1 and S6, while also augmenting AKT and ERK activation, uncovering a crosstalk between the PI3K/AKT/mTORC1 and KRAS/ERK pathways. Furthermore, CASTOR1 ablation induces genome instability, which may contribute to enhanced tumor incidence and progression. Importantly, CASTOR1 deficiency confers resistance to KRAS G12D -specific inhibitors, while over half of KRAS G12D ; C1 WT tumors also display resistance. Organoids derived from KRAS G12D ; C1 KO and KRAS G12D ; C1 WT tumors reveal a correlation between KRAS inhibitor resistance and hyperactivation of mTORC1, with mTORC1 and PI3K inhibitors sensitizing resistant tumors to KRAS G12D -targeted therapies. These findings position CASTOR1 as a novel tumor suppressor that modulates mTORC1 and KRAS signaling to constrain NSCLC progression. Our study further highlights the therapeutic potential of combining mTORC1 or ERK inhibitors with KRAS-targeted therapies for NSCLC characterized by hyperactive KRAS signaling and impaired CASTOR1 activity.

CASTOR1 functions as a tumor suppressor in NSCLC by limiting KRAS -driven tumor initiation and progression. CASTOR1 is frequently lost or inactivated in wild-type tumors during tumor progression, contributing to advanced-stage malignancies.CASTOR1 deficiency amplifies mTORC1 signaling and enhances PI3K/AKT and KRAS/ERK crosstalk, driving tumorigenesis and resistance to KRAS-specific inhibitors. Combining mTORC1 or PI3K inhibitors with KRAS-targeted therapies effectively overcomes resistance in KRAS -driven NSCLC.

In the Ras/Raf/MAPK signaling pathway, Ras and Raf proteins interact synergistically to form a tetrameric complex. NMR experiments have demonstrated that Ras dimerizes in solution and binds stably to Raf, forming Ras·Raf complexes. In this study, we constructed the ternary and quaternary complexes of KRas and CRaf based on crystal structures, denoted as (KRas)2·CRaf and (KRas)2·(CRaf)2, respectively. Molecular dynamics (MD) simulations were performed to investigate the stability of these complexes, while hydrogen bonds as well as salt bridges formed at the protein-protein interaction interfaces were analyzed based on simulation trajectories. The results revealed that the KRas·CRaf complex is more stable in explicit solvent compared with the KRas dimer. Formation of the stable quaternary complex (KRas)2·(CRaf)2 might be attributed to the association of two binary KRas·CRaf complexes. Additionally, MD simulations of the KRasG12D·CRaf complex revealed a stable and extended binding site at the KRas-CRaf interaction interface. This binding site was identified as a potential therapeutic target to block abnormal signal transmission in the pathway.

Lung cancer (LC) is one of the most common causes of cancer-related death worldwide. It has been demonstrated that the prognosis of current drug treatments is affected by a variety of factors, including late stage, tumor recurrence, inaccessibility to appropriate treatments, and, most importantly, chemotherapy resistance. Non-coding RNAs (ncRNAs) contribute to tumor development, with some acting as tumor suppressors and others as oncogenes. The phosphoinositide 3-kinase (PI3Ks)/AKT serine/threonine kinase pathway is one of the most important common targets of ncRNAs in cancer, which is widely applied to modulate the cell cycle and a variety of biological processes, including cell growth, mobility survival, metabolic activity, and protein production. Discovering the biology of ncRNA-PI3K/AKT signaling may lead to advances in cancer diagnosis and treatment. As a result, we investigated the expression and role of PI3K/AKT-related ncRNAs in clinical characteristics of lung cancer, as well as their functions as potential biomarkers in lung cancer diagnosis, prognosis, and treatment.

Background: Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS, as well as downstream MAPK pathway effectors, have shown limited clinical success. While KRAS canonically drives MAPK signaling via RAF-MEK-ERK, it is also known to play a role in PI3K-AKT signaling. Methods: Our therapeutic study targeted the PI3K pathway with the drug Omipalisib (p110α/β/δ/γ and mTORC1/2 inhibitor) in combination with two different MAPK pathway inhibitors: Trametinib (MEK1/2 inhibitor) or SHP099-HCL (SHP099; SHP2 inhibitor). Western blot analysis demonstrated that the application of Trametinib or SHP099 alone selectively blocked ERK phosphorylation (pERK) but failed to suppress phosphorylated AKT (pAKT). Conversely, Omipalisib alone successfully inhibited pAKT but failed to suppress pERK. Therefore, we hypothesized that a combination therapeutic comprised of Omipalisib with either Trametinib or SHP099 would inhibit two prominent mitogenic pathways, MAPK and PI3K-AKT, and effectively suppress PDAC growth. Results: In vitro studies demonstrated that, in several cell lines, both Omipalisib/Trametinib and Omipalisib/SHP099 combination therapeutic strategies were more effective than treatment with each drug individually at reducing proliferation, colony formation, and cell migration compared to vehicle controls. In vivo oral administration of combined Omipalisib/Trametinib treatment was significantly more effective than Omipalisib/SHP099 in reducing implanted tumor growth, and the Omipalisib/Trametinib treatment more effectively reduced tumor progression and prolonged survival in an aggressive genetically engineered mouse model of PDAC than either Omipalisib or Trametinib alone. Conclusions: Altogether, our data support a rationale for a dual treatment strategy targeting both PI3K and MAPK pathways in pancreatic cancers.

PIK3CA gene mutations have been identified in various malignancies, but the prevalence of specific mutations and their role in breast cancer development remain uncertain. This study aimed to investigate the clinicopathological significance and prognostic impact of PIK3CA mutations in breast cancer.

Five common PIK3CA mutations (H1047R and H1047L in exon 20, and E542K, E545K, and E545D in exon 9) were identified in breast cancer patients using amplification refractory mutation system (ARMS) allele-specific PCR. The study examined the relationships between these mutations and clinicopathologic factors, such as age, HR status, Her2 status, lymph node involvement, distant metastasis, clinicopathologic stage, and progression-free survival (PFS).

A total of 40 female breast cancer patients were included in this study. Twenty mutations were detected, with 12 located in exon 20 and 8 in exon 9. The most frequent mutation was H1047R in exon 20, present in 11 patients (14.8%). PIK3CA mutations were more commonly observed in patients with HR + breast cancer (P < 0.05). No significant correlation was found between PIK3CA mutations and age, Her2 status, lymph node involvement, distant metastasis, clinicopathologic stage, or Ki-67 expression. Database analysis from the cBioPortal online database showed that the median PFS (95%CI) of the PIK3CA unaltered group [22.93 (17.25-48.30) months] was higher than that of the altered group [12.98 (8.18-18.14) months]. In this study, PIK3CA mutant-type group [13.00 (10.56-15.45) months] had lower median PFS than that of the wild-type group [25.00 (13.46-36.55) months] in all breast cancer patients, the difference was significant (P = 0.004). Further, compared with PIK3CA wild-type, mutant-type was associated with poor PFS in HR + and Her2 + breast cancer patients (P < 0.05). In addition, positive H1047R mutation in PIK3CA was associated with poor PFS of breast cancer (P < 0.05).

Our data and public database research show that the PIK3CA mutation is a significant gene change in breast cancer, and the PIK3CA mutation was associated with a shorter PFS in all, HR + and Her2 + breast cancer patients. This research confirmed the important role of PIK3CA in breast cancer.

The molecular mechanisms through which endometriosis-related ovarian neoplasms (ERONs) develop from benign endometrioma remain unclear. It is especially a long-standing mystery why ovarian endometrioma has the potential to develop into two representative histological subtypes: endometrioid ovarian carcinoma or clear cell ovarian carcinoma. This study aimed to investigate the molecular carcinogenesis of ERONs using newly developed in vitro and in vivo carcinogenesis models. Epithelial cells were isolated and purified from surgically removed benign endometrioma samples, followed by immortalization by overexpressing cyclinD1/CDK4 in combination with the human TERT gene. Immortalized cells were subjected to various molecular manipulations by combining knockout or overexpression of several candidate drivers, including ARID1A, KRAS, PIK3CA, AKT, and MYC, based on previous comprehensive genome-wide studies of ERONs. These cells were then inoculated into immunocompromised mice and evaluated for malignant transformation. Inoculated cells harboring a combination of three genetic alterations successfully developed tumors with malignant features in mice, whereas those with two genetic manipulations failed to do so. Especially, ARID1A gene knockout, combined with overexpressing the KRAS oncogenic mutant allele (or overexpressing AKT) and c-Myc overexpression led to efficient tumor formation. Of note, these three combinations of genetic alterations produced tumors that histologically represented typical clear cell carcinoma in SCID mice, while the same combination led to tumors with endometrioid histology in nude mice. A combination of ARID1A mutation, KRAS mutation or AKT activation, and c-Myc overexpression were confirmed to be the main candidate drivers for the development of ERONs, as suggested by comprehensive genetic analyses of ERONs. A tumor immune microenvironment involving B-cell signaling may contribute to the diverse histological phenotypes. The present model may help to clarify the molecular mechanisms of ERON carcinogenesis and understand their histological diversity and novel molecular targets.

In non-small cell lung cancer (NSCLC), Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in up to 30% of all cases, with the most prevalent mutations occurring in codons 12 and 13. The development of KRAS-targeted drugs like sotorasib and adagrasib has generated significant excitement in the clinical arena, offering new therapeutic options. Their potential for combination with other treatments broadens the scope for clinical exploration. Acquired resistance to KRAS exon 2 p.G12C inhibitors is a significant challenge, with several reported mechanisms. In this scenario, combination therapy strategies that include targeting Src Homology Region 2 Domain-Containing Phosphatase-2 (SHP2), Son of Sevenless Homolog 1 (SOS1), or downstream effectors of KRAS exon 2 p.G12C are showing promise in overcoming such resistance. However, the efficacy of immune checkpoint inhibitors in this context still requires comprehensive evaluation. The response to anti-Programmed Cell Death Protein 1/Programmed Cell Death Protein 1 Ligand (anti-PD-1/PD-L1) drugs in NSCLC may be significantly influenced by co-occurring mutations, underscoring the need for a personalized approach to treatment based on the specific genetic profile of each tumor.

Metabolism reprogramming is a crucial hallmark of malignant tumors. Tumor cells demonstrate enhanced metabolic efficiency, converting nutrient inputs into glucose, amino acids, and lipids essential for their malignant proliferation and progression. Metformin, a commonly prescribed medication for type 2 diabetes mellitus, has garnered attention for its potential anticancer effects beyond its established hypoglycemic benefits.

This review adopts a comprehensive approach to delineate the mechanisms underlying metabolite abnormalities within the primary metabolic processes of malignant tumors.

This review examines the abnormal activation of G protein-coupled receptors (GPCRs) in these metabolic pathways, encompassing aerobic glycolysis with increased lactate production in glucose metabolism, heightened lipid synthesis and cholesterol accumulation in lipid metabolism, and glutamine activation alongside abnormal protein post-translational modifications in amino acid and protein metabolism. Furthermore, the intricate metabolic pathways and molecular mechanisms through which metformin exerts its anticancer effects are synthesized and analyzed, particularly its impacts on AMP-activated protein kinase activation and the mTOR pathway. The analysis reveals a multifaceted understanding of how metformin can modulate tumor metabolism, targeting key nodes in metabolic reprogramming essential for tumor growth and progression. The review compiles evidence that supports metformin's potential as an adjuvant therapy for malignant tumors, highlighting its capacity to interfere with critical metabolic pathways.

In conclusion, this review offers a comprehensive overview of the plausible mechanisms mediating metformin's influence on tumor metabolism, fostering a deeper comprehension of its anticancer mechanisms. By expanding the clinical horizons of metformin and providing insight into metabolism-targeted tumor therapies, this review lays the groundwork for future research endeavors aimed at refining and advancing metabolic intervention strategies for cancer treatment.

Normal cells grow and divide only when instructed to by signaling pathways stimulated by exogenous growth factors. A nearly ubiquitous feature of cancer cells is their capacity to grow independent of such signals, in an uncontrolled, cell-intrinsic manner. This property arises due to the frequent oncogenic activation of core growth factor signaling pathway components, including receptor tyrosine kinases, PI3K-AKT, RAS-RAF, mTORC1, and MYC, leading to the aberrant propagation of pro-growth signals independent of exogenous growth factors. The growth of both normal and cancer cells requires the acquisition of nutrients and their anabolic conversion to the primary macromolecules underlying biomass production (protein, nucleic acids, and lipids). The core growth factor signaling pathways exert tight regulation of these metabolic processes and the oncogenic activation of these pathways drive the key metabolic properties of cancer cells and tumors. Here, we review the molecular mechanisms through which these growth signaling pathways control and coordinate cancer metabolism.

PI3K-AKT-mTOR plays as important role in the growth, metabolism, proliferation, and migration of cancer cells, and in apoptosis, autophagy, inflammation, and angiogenesis in cancer. In this study, the aim was to comprehensively review the current research landscape regarding the PI3K-AKT-mTOR pathway in cancer, using bibliometrics to analyze research hotspots, and provide ideas for future research directions. Literature published on the topic between January 2006 and May 2023 was retrieved from the Web of Science core database, and key information and a visualization map were analyzed using CiteSpace and VOSviewer. A total of 5800 articles from 95 countries/regions were collected, including from China and the USA. The number of publications on the topic increased year on year. The major research institution was the University of Texas MD Anderson Cancer Center. Oncotarget and Clinical Cancer Research were the most prevalent journals in the field. Of 26,621 authors, R Kurzrock published the most articles, and J Engelman was cited most frequently. "A549 cell," "first line treatment," "first in human phase I," and "inhibitor" were the keywords of emerging research hotspots. Inhibitors of the PI3K-AKT-mTOR pathway and their use in clinical therapeutic strategies for cancer were the main topics in the field, and future research should also focus on PI3K-AKT-mTOR pathway inhibitors. This study is the first to comprehensively summarize trends and development s in research into the PI3K-AKT-mTOR pathway in cancer. The information that was obtained clarified recent research frontiers and directions, providing references for scholars of cancer management.

It is widely acknowledged that there is a considerable number of oncogenic mutations within the Ras superfamily of small GTPases which are the driving force behind a multitude of cancers. Ras proteins mediate a plethora of kinase pathways, including the MAPK, PI3K, and Ral pathways. Since Ras was considered undruggable until recently, pharmacological targeting of pathways downstream of Ras has been attempted to varying success, though drug resistance has often proven an issue. Nuances between kinase pathway activation in the presence of various Ras mutants are thought to contribute to the resistance, however, the reasoning behind activation of different pathways in different Ras mutational contexts is yet to be fully elucidated. Indeed, such disparities often depend on cancer type and disease progression. However, we are in a revolutionary age of Ras mutant targeted therapy, with direct-targeting KRAS-G12C inhibitors revolutionising the field and achieving FDA-approval in recent years. However, these are only beneficial in a subset of patients. Approximately 90% of Ras-mutant cancers are not KRAS-G12C mutant, and therefore raises the question as to whether other distinct amino acid substitutions within Ras may one day be targetable in a similar manner, and indeed whether better understanding of the downstream pathways these various mutants activate could further improve therapy. Here, we discuss the favouring of kinase pathways across an array of Ras-mutant oncogenic contexts and assess recent advances in pharmacological targeting of various Ras mutants. Ultimately, we will examine the utility of individualised pharmacological approaches to Ras-mediated cancer.

The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining vascular homeostasis by controlling the passage of substances and cells. In the tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives tumor angiogenesis, leading to endothelial anergy and vascular immunosuppression-a state where ECs resist cytotoxic CD8+ T cell infiltration, hindering immune surveillance. Immunotherapies have shown clinical promise. However, their effectiveness is significantly reduced by tumor EC anergy. Anti-angiogenic treatments aim to normalize tumor vessels and improve immune cell infiltration. Despite their potential, these therapies often cause significant systemic toxicities, necessitating new treatments. The small GTPase Rap1B emerges as a critical regulator of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) signaling in ECs. Our studies using EC-specific Rap1B knockout mice show that the absence of Rap1B impairs tumor growth, alters vessel morphology, and increases CD8+ T cell infiltration and activation. This indicates that Rap1B mediates VEGF-A's immunosuppressive effects, making it a promising target for overcoming vascular immunosuppression in cancer. Rap1B shares structural and functional similarities with RAS oncogenes. We propose that targeting Rap1B could enhance therapies' efficacy while minimizing adverse effects by reversing endothelial anergy. We briefly discuss strategies successfully developed for targeting RAS as a model for developing anti-Rap1 therapies.

Numerous developments have been achieved in the study and treatment of cancer throughout the decades that it has been common. After decades of research, about 100 different kinds of cancer have been found, each with unique subgroups within certain organs. This has significantly expanded our understanding of the illness. A mix of genetic, environmental, and behavioral variables contribute to the complicated and diverse process of cancer formation. Mutations, or changes in the DNA sequence, are crucial to the development of cancer. These mutations have the ability to downregulate the expression and function of Major Histocompatibility Complex class I (MHC I) and MHCII receptors, as well as activate oncogenes and inactivate tumor suppressor genes. Cancer cells use this tactic to avoid being recognized by cytotoxic CD8+T lymphocytes, which causes issues with antigen presentation and processing. This review goes into great length into the PI3K pathway, changes to MHC I, and positive impacts of tsMHC-II on disease-free survival and overall survival and the involvement of dendritic cells (DCs) in different tumor microenvironments. The vital functions that the PI3K pathway and its link to the mTOR pathway are highlighted and difficulties in developing effective cancer targeted therapies and feedback systems has also been mentioned, where resistance mechanisms include RAS-mediated oncogenic changes and active PI3K signalling.

Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib.

Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was the first pediatric study of samotolisib. The primary end point was the objective response rate; secondary end points included progression-free survival (PFS) and the recommended phase II dose and toxicity of samotolisib in children.

A total of 3.4% (41/1,206) of centrally tested patients were matched to this arm. Seventeen patients were treated. Among treated patients, the most common diagnoses included osteosarcoma (n = 6) and high-grade glioma (n = 5) harboring alterations in phosphatase and tensin homolog (n = 6), PIK3CA (n = 5), and tuberous sclerosis complex 2 (n = 3). No objective responses or prolonged stable disease were observed. Three-month PFS was 12% (95% CI, 2 to 31). Two patients experienced dose-limiting toxicities (mucositis and pneumonitis). Dose level 2 (115 mg/m2/dose twice daily) was determined to be the recommended phase II dose of samotolisib in children.

This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.

RAS proteins are conserved guanosine triphosphate (GTP) hydrolases (GTPases) that act as molecular binary switches and play vital roles in numerous cellular processes. Upon GTP binding, RAS GTPases adopt an active conformation and interact with specific proteins termed RAS effectors that contain a conserved ubiquitin-like domain, thereby facilitating downstream signaling. Over 50 effector proteins have been identified in the human proteome, and many have been studied as potential mediators of RAS-dependent signaling pathways. Biochemical and structural analyses have provided mechanistic insights into these effectors, and studies using model organisms have complemented our understanding of their role in physiology and disease. Yet, many critical aspects regarding the dynamics and biological function of RAS-effector complexes remain to be elucidated. In this review, we discuss the mechanisms and functions of known RAS effector proteins, provide structural perspectives on RAS-effector interactions, evaluate their significance in RAS-mediated signaling, and explore their potential as therapeutic targets.

NSCLC has a diverse genomic background with mutations in key proto-oncogenic drivers including Kirsten rat sarcoma (KRAS) and epidermal growth factor receptor (EGFR). Roughly 40% of adenocarcinoma harbor Kras activating mutations regardless of smoking history. Most KRAS mutations are located at G12, which include G12C (roughly 40%), G12V (roughly 20%), and G12D (roughly 15%). KRAS mutated NSCLC have higher tumor mutational burden and some have increased PD-1 expression, which has resulted in better responses to immunotherapy than other oncogenes. While initial treatment for metastatic NSCLC still relies on chemo-immunotherapy, directly targeting KRAS has proven to be efficacious in treating patients with KRAS mutated metastatic NSCLC. To date, two G12C inhibitors have been FDA-approved, namely sotorasib and adagrasib. In this review, we summarize the different drug combinations used to target KRAS G12c, upcoming G12D inhibitors and novel therapies targeting KRAS.

Lung cancer, accounting for a significant proportion of global cancer cases and deaths, poses a considerable health burden. Non-small cell lung cancer (NSCLC) patients have a poor prognosis and limited treatment options due to late-stage diagnosis and drug resistance. Dysregulated of the mitogen-activated protein kinase (MAPK) pathway, which is implicated in NSCLC pathogenesis, underscores the potential of MEK inhibitors such as binimetinib. Despite promising results in other cancers, comprehensive studies evaluating the safety and efficacy of binimetinib in lung cancer are lacking. This systematic review aimed to investigate the safety and efficacy of binimetinib for lung cancer treatment.

We searched PubMed, Scopus, Web of Science, and Google Scholar until September 2023. Clinical trials evaluating the efficacy or safety of binimetinib for lung cancer treatment were included. Studies were excluded if they included individuals with conditions unrelated to lung cancer, investigated other treatments, or had different types of designs. The quality assessment was conducted utilizing the National Institutes of Health tool.

Seven studies with 228 participants overall were included. Four had good quality judgments, and three had fair quality judgments. The majority of patients experienced all-cause adverse events, with diarrhea, fatigue, and nausea being the most commonly reported adverse events of any grade. The objective response rate (ORR) was up to 75%, and the median progression-free survival (PFS) was up to 9.3 months. The disease control rate after 24 weeks varied from 41% to 64%. Overall survival (OS) ranged between 3.0 and 18.8 months. Notably, treatment-related adverse events were observed in more than 50% of patients, including serious adverse events such as colitis, febrile neutropenia, and pulmonary infection. Some adverse events led to dose limitation and drug discontinuation in five studies. Additionally, five studies reported cases of death, mostly due to disease progression. The median duration of treatment ranged from 14.8 weeks to 8.4 months. The most common dosage of binimetinib was 30 mg or 45 mg twice daily, sometimes used in combination with other agents like encorafenib or hydroxychloroquine.

Only a few studies have shown binimetinib to be effective, in terms of improving OS, PFS, and ORR, while most of the studies found nonsignificant efficacy with increased toxicity for binimetinib compared with traditional chemotherapy in patients with lung cancer. Further large-scale randomized controlled trials are recommended.

Effectively utilizing MEK inhibitors in the clinic remains challenging due to off-target toxicity and lack of predictive biomarkers. Recent findings propose E-cadherin, a breast cancer diagnostic indicator, as a predictor of MEK inhibitor success. To address MEK inhibitor toxicity, traditional methodologies have systemically delivered nanoparticles, which require frequent, high-dose injections. Here, we present a different approach, employing a thermosensitive, biodegradable hydrogel with functionalized liposomes for local, sustained release of MEK inhibitor PD0325901 and doxorubicin. The poly(δ-valerolactone-co-lactide)-b-poly(ethylene-glycol)-b-poly(δ-valerolactone-co-lactide) triblock co-polymer gels at physiological temperature and has an optimal degradation time in vivo. Liposomes were functionalized with PR_b, a biomimetic peptide targeting the α5β1 integrin receptor, which is overexpressed in E-cadherin-positive triple negative breast cancer (TNBC). In various TNBC models, the hydrogel-liposome system delivered via local injection reduced tumor progression and improved animal survival without toxic side effects. Our work presents the first demonstration of local, sustained delivery of MEK inhibitors to E-cadherin-positive tumors alongside traditional chemotherapeutics, offering a safe and promising therapeutic strategy.

Current KRASG12C (OFF) inhibitors that target inactive GDP-bound KRASG12C cause responses in less than half of patients and these responses are not durable. A class of RASG12C (ON) inhibitors that targets active GTP-bound KRASG12C blocks ERK signaling more potently than the inactive-state inhibitors. Sensitivity to either class of agents is strongly correlated with inhibition of mTORC1 activity. We have previously shown that PI3K/mTOR and ERK-signaling pathways converge on key cellular processes and that inhibition of both pathways is required for inhibition of these processes and for significant antitumor activity. We find here that the combination of a KRASG12C inhibitor with a selective mTORC1 kinase inhibitor causes synergistic inhibition of Cyclin D1 expression and cap-dependent translation. Moreover, BIM upregulation by KRASG12C inhibition and inhibition of MCL-1 expression by the mTORC1 inhibitor are both required to induce significant cell death. In vivo, this combination causes deep, durable tumor regressions and is well tolerated. This study suggests that the ERK and PI3K/mTOR pathways each mitigate the effects of inhibition of the other and that combinatorial inhibition is a potential strategy for treating KRASG12C-dependent lung cancer.

This phase Ib study was performed to determine the safety of combination capecitabine with alpleisib (phosphatidylinositol 3-kinase catalytic subunit p110α blockade) and determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination regimen in patients with advanced solid tumors refractory to standard therapy. The synergistic anti-tumor activity and pharmacokinetics (PK) were investigated.

Dose escalation phases were conducted in patients with advanced solid cancers who were refractory to standard therapy regardless of PIK3CA mutation. Patients were administered orally once daily alpelisib (200mg and 300mg) and twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1-14) every 3 weeks. Standard "3 + 3" dose escalation was used to define the MTD. The effect of alpelisib on the PK of capecitabine was assessed.

Patients with 6 colorectal cancer (three PIK3CA mutation) and 6 breast cancer (all PIK3CA mutation) were enrolled. The first three patients in dose level 0 (alpelisib 200mg daily, capecitabine 1,000 mg/m2 twice daily) had no dose-limiting toxicities (DLTs). In dose level 1 (alpelisib increased to 300 mg daily, capecitabine 1,000mg twice daily), one of six patients had DLT (grade (Gr) 3 hyperglycemia). When dose level 2 (alpelisib 300mg daily, capecitabine 1,250 mg/m2 twice daily) was expanded to 3 patients, no patients had DLTs. The combination of alpelisib 300mg daily and capecitabine 1,250 mg/m2 twice daily was declared as the MTD/RP2D in patients with advanced solid tumors. The most common AEs were Gr 1-3 hyperglycemia (75.0%). Frequent all-grade, treatment-related AEs included Gr 2-3 nausea (75.0%), Gr 1-2 diarrhea (50.0%), Gr 1-2 hand-foot syndrome (41.7%), Gr 1-2 anorexia (41.7%), Gr 2 mucositis (33.3%). Antitumor activity was observed in patients with PIK3CA mutant breast cancer (3 partial response and 3 stable disease of total 6 patients). Alpelisib exposure (Cmax and AUC0-12) was unaffected by concomitant capecitabine. There were no clinically relevant drug-drug interactions observed between alpelisib and capecitabine.

The combination of alpelisib and capecitabine is generally tolerated, without pharmacokinetic interactions, and shows antitumor activity in patients with PIK3CA mutant advanced cancers.

The Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the first driver oncogenes identified in human cancer in the early 1980s. However, it has been deemed 'undruggable' for nearly four decades until the discovery of KRAS G12C covalent inhibitors, which marked a pivotal breakthrough. Currently, sotorasib and adagrasib have been approved by the US FDA to treat patients with non-small cell lung cancer (NSCLC) harboring KRAS G12C mutation. However, their efficacy is somewhat limited compared to that of other targeted therapies owing to intrinsic resistance or early acquisition of resistance. While G12C is the predominant subtype of KRAS mutations in NSCLC, G12D/V is prevalent in colorectal and pancreatic cancers. These facts have spurred active research to develop more potent KRAS G12C inhibitors as well as inhibitors targeting non-G12C KRAS mutations. Novel approaches, such as molecular shielding or targeted protein degradation, are also under development. Combining KRAS inhibitors with inhibitors of the receptor-tyrosine kinase-RAS-mitogen-activated protein kinase (MAPK) pathway is underway to counteract redundant feedback mechanisms. Additionally, immunological approaches utilizing T-cell receptor (TCR)-engineered T cell therapy or vaccines, and Hapimmune antibodies are ongoing. This review delineates the recent advancements in KRAS inhibitor development in the post-sotorasib/adagrasib era, with a focus on NSCLC.

The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the three kinases (PI3K, AKT, and mTOR). Although multiple compounds have been developed, at present, there are just three inhibitors approved to target this pathway in patients with advanced ER-positive, HER2-negative breast cancer: everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor). Like most targeted cancer drugs, resistance poses a major problem in the clinical setting and is a factor that has frequently limited the overall efficacy of these agents. Drug resistance can be categorised into intrinsic or acquired resistance depending on the timeframe it has developed within. Whereas intrinsic resistance exists prior to a specific treatment, acquired resistance is induced by a therapy. The majority of patients with ER-positive, HER2-negative advanced breast cancer will likely be offered an inhibitor of the PI3K/AKT/mTOR pathway at some point in their cancer journey, with the options available depending on the approval criteria in place and the cancer's mutation status. Within this large cohort of patients, it is likely that most will develop resistance at some point, which makes this an area of interest and an unmet need at present. Herein, we review the common mechanisms of resistance to agents that target the PI3K/AKT/mTOR signalling pathway, elaborate on current management approaches, and discuss ongoing clinical trials attempting to mitigate this significant issue. We highlight the need for additional studies into AKT1 inhibitor resistance in particular.

Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.

Personalized medicine is a new approach toward safer and even cheaper treatments with minimal side effects and toxicity. Planning a therapy based on individual properties causes an effective result in a patient's treatment, especially in a complex disease such as cancer. The benefits of personalized medicine include not only early diagnosis with high accuracy but also a more appropriate and effective therapeutic approach based on the unique clinical, genetic, and epigenetic features and biomarker profiles of a specific patient's disease. In order to achieve personalized cancer therapy, understanding cancer biology plays an important role. One of the crucial applications of personalized medicine that has gained consideration more recently due to its capability in developing disease therapy is related to the field of stem cells. We review various applications of pluripotent, somatic, and cancer stem cells in personalized medicine, including targeted cancer therapy, cancer modeling, diagnostics, and drug screening. CRISPR-Cas gene-editing technology is then discussed as a state-of-the-art biotechnological advance with substantial impacts on medical and therapeutic applications. As part of this section, the role of CRISPR-Cas genome editing in recent cancer studies is reviewed as a further example of personalized medicine application.

Phosphatase and tensin homolog (PTEN) loss-of-function/PI3K pathway hyperactivation is associated with poor therapeutic outcomes and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies in Pb-Cre;PTENfl/flTrp53fl/fl genetically engineered mice (GEM) with aggressive-variant prostate cancer (AVPC) demonstrated tumor growth control in 60% mice following androgen deprivation therapy/PI3K inhibitor (PI3Ki)/programmed cell death protein 1 (PD-1) antibody combination, via abrogating lactate cross-talk between cancer cells and tumor-associated macrophages (TAM), and suppression of histone lactylation (H3K18lac)/phagocytic activation within TAM. Here, we targeted immunometabolic mechanism(s) of PI3Ki resistance, with the goal of durable tumor control in AVPC.

Pb-Cre;PTENfl/flTrp53fl/fl GEM were treated with PI3Ki (copanlisib), MEK inhibitor (trametinib) or Porcupine inhibitor (LGK'974) singly or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ex vivo coculture mechanistic studies were performed on GEM tumors or corresponding tumor-derived cell lines.

Given our proteomic profiling showing persistent MEK signaling within tumors of PI3Ki-resistant GEM, we tested whether addition of trametinib to copanlisib enhances tumor control in GEM, and we observed 80% overall response rate via additive suppression of lactate within TME and H3K18lac within TAM, relative to copanlisib (37.5%) monotherapy. The 20% resistant mice demonstrated feedback Wnt/β-catenin activation, resulting in restoration of lactate secretion by tumor cells and H3K18lac within TAM. Cotargeting Wnt/β-catenin signaling with LGK'974 in combination with PI3Ki/MEKi, demonstrated durable tumor control in 100% mice via H3K18lac suppression and complete TAM activation.

Abrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials.

Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-related death worldwide. The purpose of this study was to discover novel molecular pathways and potential prognosis biomarkers. To achieve this, we acquired five microarray datasets from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes between CRC and adjacent normal tissue samples and further validated them using The Cancer Genome Atlas (TCGA) database. Using various analytical approaches, including the construction of a competing endogenous RNA (ceRNA) network, Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway analyses, as well as survival analysis, we identified key genes and pathways associated with the diagnosis and prognosis of CRC. We obtained a total of 185 differentially expressed genes, comprising 17 lncRNAs, 30 miRNAs, and 138 mRNAs. The ceRNA network consisted of 17 lncRNAs, 25 miRNAs, and 7 mRNAs. Among the 7 mRNAs involved in the ceRNA network, SLC7A5 and KRT80 were found to be upregulated, while ADIPOQ, CCBE1, KCNB1, CADM2, and CHRDL1 were downregulated in CRC. Further analysis revealed that ADIPOQ and SLC7A5 are involved in the AMPK and mTOR signaling pathway, respectively. In addition, survival analysis demonstrated a statistically significant relationship between ADIPOQ, SLC7A5, and overall survival rates in CRC patients. In conclusion, our findings suggest that downregulation of ADIPOQ and upregulation of SLC7A5 in tumor cells lead to increased mTORC1 activity, reduced autophagy, enhanced angiogenesis, and ultimately contribute to cancer progression and decreased survival in CRC patients.

Cancer malignancies may broadly be described as heterogeneous disorders manifested by uncontrolled cellular growth/division and proliferation. Tumor cells utilize metabolic reprogramming to accomplish the upregulated nutritional requirements for sustaining their uncontrolled growth, proliferation, and survival. Metabolic reprogramming also called altered or dysregulated metabolism undergoes modification in normal metabolic pathways for anabolic precursor's generation that serves to continue biomass formation that sustains the growth, proliferation, and survival of carcinogenic cells under a nutrition-deprived microenvironment. A wide range of dysregulated/altered metabolic pathways encompassing different metabolic regulators have been described; however, the current review is focused to explain deeply the metabolic pathways modifications inducing upregulation of proteins/amino acids metabolism. The essential modification of various metabolic cycles with their consequent outcomes meanwhile explored promising therapeutic targets playing a pivotal role in metabolic regulation and is successfully employed for effective target-specific cancer treatment. The current review is aimed to understand the metabolic reprogramming of different proteins/amino acids involved in tumor progression along with potential therapeutic perspective elucidating targeted cancer therapy via these targets.

Lung adenocarcinoma (LUAD) is the most common lung cancer, which accounts for about 35-40% of all lung cancer patients. Despite therapeutic advancements in recent years, the overall survival time of LUAD patients still remains poor, especially KRAS mutant LUAD. Therefore, it is necessary to further explore novel targets and drugs to improve the prognos is for LUAD. Ferroptosis, an iron-dependent regulated cell death (RCD) caused by lipid peroxidation, has attracted much attention recently as an alternative target for apoptosis in LUAD therapy. Ferroptosis has been found to be closely related to LUAD at every stage, including initiation, proliferation, and progression. In this review, we will provide a comprehensive overview of ferroptosis mechanisms, its regulation in LUAD, and the application of targeting ferroptosis for LUAD therapy.

Undruggable proteins are a class of proteins that are often characterized by large, complex structures or functions that are difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also a great opportunity for treatment of human diseases and has attracted substantial efforts in the field of medicine. Therefore, in this review, we focus on the recent development of drug discovery targeting "undruggable" proteins and their application in clinic. To make this review well organized, we discuss the design strategies targeting the undruggable proteins, including covalent regulation, allosteric inhibition, protein-protein/DNA interaction inhibition, targeted proteins regulation, nucleic acid-based approach, immunotherapy and others.

Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS as well as its target MAPK pathway effectors have shown limited success due to the difficulty to pharmacologically target KRAS, inherent drug resistance in PDAC cells, and acquired resistance through activation of alternative mitogenic pathways such JAK-STAT and PI3K-AKT. While KRAS canonically drives the MAPK signaling pathway via RAF-MEK-ERK, it is also known to play a role in PI3K-AKT signaling. Our therapeutic study targeted the PI3K-AKT pathway with the drug Omipalisib (p110α/β/δ/γ and mTORC1/2 inhibitor) in combination with MAPK pathway targeting drug Trametinib (MEK1/2 inhibitor) or SHP099-HCL (SHP099), which is an inhibitor of the KRAS effector SHP2. Western blot analysis demonstrated that application of Trametinib or SHP099 alone selectively blocked ERK phosphorylation (pERK) but failed to suppress phosphorylated AKT (pAKT) and in some instances increased pAKT levels. Conversely, Omipalisib alone successfully inhibited pAKT but failed to suppress pERK. Therefore, we hypothesized that a combination therapeutic comprised of Omipalisib with either Trametinib or SHP099 would inhibit two prominent mitogenic pathways, MEK and PI3K-AKT, to more effectively suppress pancreatic cancer. In vitro studies demonstrated that both Omipalisib/Trametinib and Omipalisib/SHP099 combination therapeutic strategies were generally more effective than treatment with each drug individually at reducing proliferation, colony formation, and cell migration compared to vehicle controls. Additionally, we found that while combination Omipalisib/SHP099 treatment reduced implanted tumor growth in vivo , the Omipalisib/Trametinib treatment was significantly more effective. Therefore, we additionally tested the Omipalisib/Trametinib combination therapeutic in the highly aggressive PKT (Ptf1a cre , LSL-Kras G12D , TGFbR2 fl/fl ) spontaneous mouse model of PDAC. We subsequently found that PKT mice treated with the Omipalisib/Trametinib combination therapeutic survived significantly longer than mice treated with either drug alone, and more than doubled the mean survival time of vehicle control mice. Altogether, our data support the importance of a dual treatment strategy targeting both MAPK and PI3K-AKT pathways.

Lung cancer continues to be the leading cause of cancer-related death worldwide. In the last decade, significant advancements in the diagnosis and treatment of lung cancer, particularly NSCLC, have been achieved with the help of molecular translational research. Among the hopeful breakthroughs in therapeutic approaches, advances in targeted therapy have brought the most successful outcomes in NSCLC treatment. In targeted therapy, antagonists target the specific genes, proteins, or the microenvironment of tumors supporting cancer growth and survival. Indeed, cancer can be managed by blocking the target genes related to tumor cell progression without causing noticeable damage to normal cells. Currently, efforts have been focused on improving the targeted therapy aspects regarding the encouraging outcomes in cancer treatment and the quality of life of patients. Treatment with targeted therapy for NSCLC is changing rapidly due to the pace of scientific research. Accordingly, this updated study aimed to discuss the tumor target antigens comprehensively and targeted therapy-related agents in NSCLC. The current study also summarized the available clinical trial studies for NSCLC patients.