Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common mutations in human cancers and overgrowth syndromes. The ubiquitous expression of the activating Pik3caH1047R mutation results in reduced survival, organomegaly, hypoglycaemia and hypoinsulinemia in mice. Here we demonstrate that in vivo expression of Pik3caH1047R attenuates the rise in blood glucose in response to oral glucose administration, stimulates glucose uptake in peripheral tissues, inhibits hepatic gluconeogenesis and pancreatic insulin secretion, and increases adipose lipolysis and white adipose tissue browning. Together, our data reveal that the systemic activation of the PI3K pathway in mice disrupts glucose homeostasis through the regulation of hepatic gluconeogenesis, and leads to increased lipolysis of adipose tissue.

Neglected tropical diseases (NTDs), including Chagas disease, human African trypanosomiasis (HAT), leishmaniasis, and malaria, remain a major global health challenge, disproportionately affecting low-income populations. Current therapies for these diseases suffer from significant limitations, such as reduced efficacy, high toxicity, and emerging parasite resistance, highlighting the urgent need for new therapeutic strategies. In response, substantial efforts have been directed toward the synthesis of new molecules with improved potency, selectivity, and pharmacokinetic profiles. However, despite many of these compounds exhibiting favorable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles and strong in vitro activity, their translation into in vivo models remains limited. Key challenges include the lack of investment, the absence of fully representative experimental models, and difficulties in extrapolating cell-based assay results to more complex biological systems. In this review, we analyzed the latest advancements (2019-2024) in the development of these compound classes, correlating predictive parameters with their observed biological activity. Among these parameters, we highlighted the partition coefficient (LogP), which measures a compound's lipophilicity and influences its ability to cross biological membranes, and Caco-2 cell permeability, an in vitro model widely used to predict intestinal drug absorption. Additionally, we prioritized the most promising molecules and structural classes for pharmaceutical development, discussing structure-activity relationships (SARs) and the remaining challenges that must be overcome to enable the clinical application of these compounds in the treatment of NTDs.

Matched targeted therapies (MTT) given alone or in combination with systemic anti-cancer therapies have delivered proven survival benefit for many people with newly diagnosed cancer. However, there is little evidence of their effectiveness in the recurrent or late-stage setting. With this uncertainty, alongside the perception that late-stage cancers are too genetically heterogenous or too mutationally diverse to benefit from matched targeted therapies, next-generation sequencing (NGS) of tumours in people with refractory cancer remains a low priority. As a result, next-generation sequencing testing of recurrent or late-stage disease is discouraged. We lack evidence to support the utility of next generation sequencing in guiding matched targeted therapies in this setting.

To evaluate the benefits and harms of matched targeted therapies in people with advanced cancers in randomised controlled trials.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organisation International Clinical Trials Registry Platform (WHO-ICTRP) search portal up to 30th October 2024. We also screened reference lists of included studies and also the publications that cited these studies.

We included randomised controlled trials (RCTs) that had enroled participants with advanced/refractory solid or haematological cancers who had progressed through at least one line of standard anti-cancer systemic therapy. To be eligible, all participants should have received matched targeted therapy based on next-generation sequencing carried out on their tumour (tumour tissue, blood or bone marrow).

We systematically searched medical databases (e.g. MEDLINE, Embase) and trial registers for randomised controlled trials (RCTs). Outcomes of interest were progression-free survival (PFS), overall survival (OS), overall response rates (ORR), serious (grade 3 or 4) adverse events (AEs) and quality of life (QOL). We used a random-effects model to pool outcomes across studies and compared predefined subgroups using interaction tests. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment of certainty was used to evaluate the quality of evidence.

We identified a total of 37 studies, out of which 35 studies (including 9819 participants) were included in the meta-analysis. All included studies compared a matched targeted therapy intervention to standard-of-care treatment, non-matched targeted therapies or no treatment (best supportive care): Matched targeted therapy versus standard-of-care treatment Matched targeted therapy (MTT) compared with standard systematic therapy probably reduces the risk of disease progression by 34% (hazard ratio (HR) = 0.66, 95% confidence interval (CI) 0.59 to 0.74; 14 studies, 3848 participants; moderate-certainty evidence). However, MTT might have little to no difference in risk of death (HR = 0.85, 95% CI 0.75 to 0.97; 14 studies, 3848 participants; low-certainty evidence) and may increase overall response rates (low-certainty evidence). There was no clear evidence of a difference in severe (grade 3/4) adverse events between matched targeted therapy and standard-of-care treatment (low-certainty evidence). There was limited evidence of a difference in quality of life between groups (very low-certainty of evidence). Matched targeted therapy in combination with standard-of-care treatment versus standard-of-care treatment alone Matched targeted therapy in combination with standard-of-care treatment compared with standard-of-care treatment alone probably reduces the risk of disease progression by 39% (HR = 0.61, 95% CI 0.53-0.70, 14 studies, 2,637 participants; moderate-certainty evidence) and risk of death by 21% (HR = 0.79, 95% CI 0.70 to 0.89; 11 studies, 2575 participants, moderate-certainty evidence). The combination of MTT and standard-of-care treatment may also increase overall response rates (low-certainty evidence). There was limited evidence of a difference in the incidence of severe adverse events (very low-certainty evidence) and quality of life between the groups (very low-certainty of evidence). Matched targeted therapy versus non-matched targeted therapy Matched targeted therapy compared with non-matched targeted therapy probably reduces the risk of disease progression by 24% (HR = 0.76, 95% CI 0.64 to 0.89; 3 studies, 1568 participants; moderate-certainty evidence) and may reduce the risk of death by 25% (HR = 0.75, 95% CI 0.65 to 0.86, 1307 participants; low-certainty evidence). There was little to no effect on overall response rates between MTT and non-MTT. There was no clear evidence of a difference in overall response rates (low-certainty evidence) and severe adverse events between MTT and non-MTT (low-certainty evidence). None of the studies comparing MTT and non-MTT reported quality of life. Matched targeted therapy versus best supportive care Matched targeted therapy compared with the best supportive care (BSC) i.e. no active treatment probably reduces the risk of disease progression by 63% (HR 0.37, 95% CI 0.28 to 0.50; 4 studies, 858 participants; moderate-certainty evidence). There was no clear evidence of a difference in overall survival between groups (HR = 0.88, 95% CI 0.73 to 1.06, 3 studies, 783 participants; low-certainty evidence). There was no clear evidence of a difference in overall response rates (very low-certainty of evidence) and incidence of severe adverse events (very low-certainty of evidence) between the groups. Quality of life was reported in a single study but did not provide composite scores. Risk of bias The overall risk of bias was judged low for eight studies, unclear for two studies, and the remaining 27 studies were high risk.

Matched targeted therapies guided by next-generation sequencing in people with advanced cancer prolongs the time before cancer progresses compared to standard therapies. However, there is limited evidence to suggest that it prolongs overall survival, improves the quality of life or increases adverse events. Importantly, this review supports equitable access to next-generation sequencing technology for all people with advanced cancer and offers them the opportunity to access genotype-matched targeted therapies.

Activating PIK3CA mutations, present in up to 40% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (Her2-) breast cancer (BC) patients, can be effectively targeted with the alpha isoform-specific PI3K inhibitor Alpelisib. This treatment significantly improves outcomes for HR+, Her2-, and PIK3CA-mutated metastatic BC patients. However, acquired resistance, often due to aberrant activation of the mTOR complex 1 (mTORC1) pathway, remains a significant clinical challenge. Our study, using in vitro and orthotopic xenograft mouse models, demonstrates that constitutively active mTORC1 signaling renders PI3K inhibitor-resistant BC exquisitely sensitive to various drugs targeting cancer metabolism. Mechanistically, mTORC1 suppresses the induction of autophagy during metabolic perturbation, leading to energy stress, a critical depletion of aspartate, and ultimately cell death. Supporting this mechanism, BC cells with CRISPR/Cas9-engineered knockouts of canonical autophagy genes showed similar vulnerability to metabolically active drugs. In BC patients, high mTORC1 activity, indicated by 4E-BP1T37/46 phosphorylation, correlated with p62 accumulation, a sign of impaired autophagy. Together, these markers predicted poor overall survival in multiple BC subgroups. Our findings reveal that aberrant mTORC1 signaling, a common cause of PI3K inhibitor resistance in BC, creates a druggable metabolic vulnerability by suppressing autophagy. Additionally, the combination of 4E-BP1T37/46 phosphorylation and p62 accumulation serves as a biomarker for poor overall survival, suggesting their potential utility in identifying BC patients who may benefit from metabolic therapies.

This article provides a comprehensive analysis of the signaling pathways implicated in breast cancer (BC), the most prevalent malignancy among women and a leading cause of cancer-related mortality globally. Special emphasis is placed on the structural dynamics of protein complexes that are integral to the regulation of these signaling cascades. Dysregulation of cellular signaling is a fundamental aspect of BC pathophysiology, with both upstream and downstream signaling cascade activation contributing to cellular process aberrations that not only drive tumor growth, but also contribute to resistance against current treatments. The review explores alterations within these pathways across different BC subtypes and highlights potential therapeutic strategies targeting these pathways. Additionally, the influence of specific mutations on therapeutic decision-making is examined, underscoring their relevance to particular BC subtypes. The article also discusses both approved therapeutic modalities and ongoing clinical trials targeting disrupted signaling pathways. However, further investigation is necessary to fully elucidate the underlying mechanisms and optimize personalized treatment approaches.

Peritoneal carcinomatosis in ovarian cancer is often associated with ascites where cancer cells grow as aggregates. Given the emerging evidence that multicellular growth enhances resistance to conventional therapies, and that patients frequently develop resistance to platinum salts, we investigated the efficiency of PI3K/Akt signalling pathway targeting in multicellular growth and its importance as a potential therapeutic target in cells resistant to platinum salts. Due to its importance in many cancers and to the frequent mutations of its encoding gene PIK3CA, we focused on targeting PI3Kα using BYL-719 (Alpelisib), an isoform-specific inhibitor already used in clinics. We used a panel of 3 ovarian cancer cell lines, SKOV-3, EFO-21 and OVCAR-3, which come from different histological origins and bear different mutations. PI3K targeting drugs inhibit the activity of the PI3K/Akt pathway in all tested ovarian cancer cell lines with a drastic reduction of the phosphorylation of Akt on the serine 473, regardless the histology or the mutational profile. We showed that when cultured in 3D aggregates, ovarian cancer cells are more resistant to the PI3Kα-specific inhibitor BYL-719 and cisplatin compared to 2D monolayers. BYL-719 synergizes with cisplatin in 3D cultures only in PIK3CA-mutated SKOV-3 cells. This drug combination leads to a major cytotoxicity in 3D aggregates of this cell line. Finally, BYL-719 in combination with cisplatin remains active in 3D aggregates of SKOV-3 cells co-cultured with mesenchymal stem cells. We have identified a signalling pathway of interest for the treatment of advanced ovarian cancer in vitro, which could limit the progression of this disease. These data pave the road to investigate whether PI3Kα-specific inhibitor BYL-719 should be proposed in combination with cisplatin, in priority in patients bearing a PIK3CA mutation.

Platinum-based chemotherapeutics, such as cisplatin and carboplatin, are widely used to treat various malignancies. However, the development of chemoresistance remains a significant challenge, limiting their efficacy. This review explores the multifaceted mechanisms of platinum-based chemoresistance, with a particular focus on the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, which plays a critical role in promoting tumor survival and resistance to platinum compounds. Additionally, we examined the role of phosphatidic acid (PA) and its synthesizing enzymes, phospholipase D (PLD) and lysophosphatidic acid acyltransferase (LPAAT), in the regulation of mTORC1 activity. Given the involvement of mTORC1 in chemoresistance, we evaluated the potential of mTOR inhibitors as a therapeutic strategy to overcome platinum resistance. Finally, we discuss combination therapies targeting the mTOR pathway alongside conventional chemotherapy to improve treatment outcomes. This review highlights the potential of targeting mTORC1 and related pathways to improve therapeutic strategies for chemoresistant cancers.

Globally, Breast Cancer (BC) is the most frequent cancer in women and has a major negative impact on the physical and emotional well-being of its patients as well as one of the most common cancers to be diagnosed. Numerous studies have been published to identify various molecular pathways, including PI3K/AKT/PTEN. Moreover, growing evidence suggests that miRNAs have been found to play a vital role in the growth and carcinogenesis of tumors. Because of their crucial in the development and course of the illness, all other molecular variables, molecular pathways and microRNAs have gained recognition as important therapeutic targets in BC due to growing interest among researchers in utilizing synthetic drugs and natural products to target these signaling pathway with encouraging outcomes in vivo, in vitro and preclinical trials in recent years.

We searched PUBMED, Science Direct, google scholar, Embase and Scopus for article published from the inception of each database to May 30, 2024.

We discussed PI3K/PTEN/AKT signaling pathway and microRNA activities with breast cancer cell line. In addition, this review covered a wide range of potential drug and natural products as targeted therapies that are linked to downregulating ER-α expression and activity, inhibiting proliferation, migration, metastasis and angiogenesis, inducing apoptosis, cell cycle arrest and sensitizing breast cancer cells. Many studies have been conducted, but as of right now, there are not enough articles to fully explain the treatment and research of breast cancer.

We also need more and more studies on breast cancer from a variety of perspectives. Future scientist will find it easier to consider breast cancer treatment after reading this article presentation. So, the review focuses on our understanding of the roles that microRNA and PI3/PTEN/AKT signaling pathways play in regulating BC. Furthermore, we emphasized the potential therapeutic benefits of newly discovered inhibitors and the use of natural compounds in alone or combinations during preclinical trials.

Alpelisib is a phosphatidylinositol 3-kinase inhibitor used to treat certain hormone therapy resistant breast cancers that can cause hyperglycemia through inhibition of the insulin signaling cascade. Diabetic ketoacidosis with the initiation of alpelisib remains a rare complication. The objective of this report is to describe a patient with alpelisib-induced diabetic ketoacidosis and the difficulties of management.

A 59-year-old woman was admitted to the hospital with a history of noninsulin dependent type 2 diabetes on metformin presented with diabetic ketoacidosis. One month prior to this hospitalization, the patient was started on alpelisib. On presentation, blood glucose level was 612 mg/dL and hemoglobin A1c level was 11.9% (107 mmol/mol), a 4.6% (27 mmol/mol) increase from 2 months prior. The patient was started on intravenous insulin and alpelisib was held resulting in rapid resolution of the patient's hyperglycemia and ketoacidosis. However, with reinitiation of alpelisib the patient developed worsening hyperglycemia. Relative glycemic control was ultimately obtained with 3 oral agents and high doses of insulin.

Direct inhibition of insulin signaling by alpelisib leads to insulin-resistant hyperglycemia. Most cases can be controlled with oral agents; however, insulin therapy is required in rare instances. Although more effective for glycemic control, insulin therapy has the potential to decrease the antitumor effects of alpelisib.

Diabetic ketoacidosis is a rare complication of alpelisib initiation, which is quickly resolved with cessation of the agent. For patients where cessation is not an option, insulin and insulin sensitizing agents can be used to achieve glycemic control at the potential detriment of tumor treatment.

The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for cancer. Thiazole derivatives have been reported to have diverse biological activities, especially in terms of anti-tumor. Consequently, we hypothesized that the introduction of a thiazole functional group in PD was likely to improve the biological potency. Here, three series of PD derivatives containing a thiazole moiety were synthesized, including (a) sulfonyl-containing thiazole derivatives (5 a-l), (b) urea-containing thiazole derivatives (7 a-i), and (c) thiourea-containing thiazole derivatives (9 a-i), and evaluated for HIF-1α inhibitory activity using a Hep3B cell-based luciferase reporter assay. The results showed that about 1/3 of the target compounds showed moderate or strong HIF-1α inhibitory activity, among which compounds 5 d and 7 b showed the strongest inhibitory activity with IC50 values of 17.37 and 6.42 μM, respectively, and did not show any significant cytotoxicity. Western blot assay results indicated that these two compounds exhibited more potent inhibition, compared with panaxadiol, of the expression of HIF-1α protein in Hep3B cells at a concentration of 50 μM. Molecular docking experiments were also performed to investigate the structure-activity relationship. Compounds 5 d and 7 b can be used as leads for further study and development of novel antitumor drugs.

Alpelisib is an oral α-specific class I PI3K inhibitor approved in combination with fulvestrant for the treatment of PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. The tolerability of this drug with the oral chemotherapy capecitabine is unknown.

This phase I trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of alpelisib (250 mg or 300 mg daily for 3-weeks) with capecitabine (1000 mg/m2 twice daily for 2-weeks followed by a 1-week rest period) in patients with metastatic HER2-negative breast cancer, regardless of PIK3CA mutation status.

Eighteen patients were treated with alpelisib-capecitabine. Half of the patients had HR+ breast cancer, and 16 had prior systemic therapy for metastatic disease. The MTD of alpelisib was 250 mg daily in combination with capecitabine 1000 mg/m2 twice daily. DLTs included hyperglycemia, QTc prolongation, fatigue, and chest pain. The most common grade 3 adverse event (AE) was hyperglycemia (28%). No grade 4 AEs were observed. Three patients discontinued therapy due to an AE. One-third of patients required dose reduction of both alpelisib and capecitabine. Four patients experienced a partial response and 8 patients experienced stable disease. The median progression-free survival was 9.7 months (95% CI 2.8-13.5 months) and median overall survival was 18.2 months (95% CI 7.2-35.2 months). Twelve patients had PIK3CA mutation testing completed, of these 2 had known or likely deleterious PIK3CA mutation.

This study provides safety data for an oral combination therapy of alpelisib-capecitabine and defines tolerable doses for further study.

Phosphoinositide 3-kinase (PI3K) is responsible for phosphorylating phosphoinositides to generate secondary signaling molecules crucial for regulating various cellular processes, including cell growth, survival, and metabolism. The PI3K is a heterodimeric enzyme complex comprising of a catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit (p85). The binding of the regulatory subunit, p85, with the catalytic subunit, p110, forms an integral component of the PI3K enzyme. PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) belongs to class IA of the PI3K family. PIK3R1 exhibits structural complexity due to alternative splicing, giving rise to distinct isoforms, prominently p85α and p55α. While the primary p85α isoform comprises multiple domains, including Src homology 3 (SH3) domains, a Breakpoint Cluster Region Homology (BH) domain, and Src homology 2 (SH2) domains (iSH2 and nSH2), the shorter isoform, p55α, lacks certain domains present in p85α. In this review, we will highlight the intricate regulatory mechanisms governing PI3K signaling along with the impact of PIK3R1 alterations on cellular processes. We will further delve into the clinical significance of PIK3R1 mutations in various cancer types and their implications for prognosis and treatment outcomes. Additionally, we will discuss the evolving landscape of targeted therapies aimed at modulating PI3K-associated pathways. Overall, this review will provide insights into the dynamic interplay of PIK3R1 in cancer, fostering advancements in precision medicine and the development of targeted interventions.

Bladder cancer is a leading cancer type in men. The complexity of treatment in late-stage bladder cancer after systemic spread through the lymphatic system highlights the importance of modulating disease-free progression as early as possible in cancer staging. With current therapies relying on previous standards, such as platinum-based chemotherapeutics and immunomodulation with Bacillus Calmette-Guerin, researchers, and clinicians are looking for targeted therapies to stop bladder cancer at its source early in progression. A new era of molecular therapies that target specific features upregulated in bladder cancer cell lines is surfacing, which may be able to provide clinicians and patients with better control of disease progression. Here, we discuss multiple emerging therapies including immune checkpoint inhibitors of the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway, antibody-drug conjugates, modulation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) cell proliferation pathway, chimeric antigen receptor T-cell therapy, and fibroblast growth factor receptor targeting. Together, these modern treatments provide potentially promising results for bladder cancer patients with the possibility of increasing remission and survival rates.

The results of the SOLAR-1 and CAPItello-291, highlight the benefit of the ɑ-selective phosphoinositide 3-Kinase Pathway inhibitor (PI3Ki) alpelisib and the AKT inhibitor (AKTi) capivasertib in patients with hormone receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2 (HER2)- negative metastatic breast cancer (mBC) that have PIK3CA/AKT1/PTEN tumour alterations. Although effective, these drugs are associated with significant toxicities, which often limit their use, particularly in frail patients. Following the recent incorporation of these agents into clinical practice, and with many others currently in development, significant challenges have emerged, particularly those regarding biomarkers for patient selection. This review will discuss biomarkers of response and their resistance to PI3K/AKT inhibitors (PI3K/AKTis) in HR+/HER- BC in early and advanced settings to ascertain which populations will most benefit from these drugs. Of the biomarkers that were analysed, such as PIK3CA, AKT, PTEN mutations, insulin levels, 18 F-FDG-PET/TC, only the PIK3CA-mutations (PIK3CA-mut) and the AKT pathway alterations seem to have a predictive value for treatments with alpelisib and capivasertib. However, due to the retrospective and exploratory nature of the study, the data did not provide conclusive results. In addition, the different methods used to detect PIK3CA/AKT1/PTEN alterations underline the fact that the optimal diagnostic companion has yet to be established. We have summarised the clinical data on the approved and discontinued agents targeting this pathway and have assessed the drugs development, successes, and failures. Finally, because of tumour heterogeneity, we emphasise the importance of reassessing the mutational status of PI3KCA in both metastatic tissue and blood at the time of disease progression to better tailor treatment for patients.

Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.

The incidence of nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is increasing in adults and children. Unfortunately, effective pharmacological treatments remain unavailable. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase domain-containing protein (PNPLA3 I148M) have the most significant genetic association with the disease at all stages of its progression. A roadblock to identifying potential treatments for PNPLA3-induced NAFLD is the lack of a human cell platform that recapitulates the PNPLA3 I148M-mediated onset of lipid accumulation. Hepatocyte-like cells were generated from PNPLA3-/- and PNPLA3I148M/M-induced pluripotent stem cells (iPSCs). Lipid levels were measured by staining with BODIPY 493/503 and were found to increase in PNPLA3 variant iPSC-derived hepatocytes. A small-molecule screen identified multiple compounds that target Src/PI3K/Akt signaling and could eradicate lipid accumulation in these cells. We found that drugs currently in clinical trials for cancer treatment that target the same pathways also reduced lipid accumulation in PNPLA3 variant cells.

Lung metastasis of breast cancer is rapidly becoming a thorny problem in the treatment of patients with breast cancer and an obstacle to long-term survival. The main challenges of treatment are the absence of therapeutic targets and drug resistance, which promotes the development of nanotechnology in the diagnosis and treatment process. Taking advantage of the controllability and targeting of nanotechnology, drug-targeted delivery, controlled sustained release, multi-drug combination, improved drug efficacy, and reduced side effects can be realized in the process of the diagnosis and treatment of metastatic breast cancer (MBC). Several nanotechnology-based theranostic strategies have been investigated in breast cancer lung metastases (BCLM): targeted drug delivery, imaging analysis, immunotherapy, gene therapy, and multi-modality combined therapy, and some clinical applications are in the research phase. In this review, we present current nanotechnology-based diagnosis and treatment approaches for patients of incurable breast cancer with lung metastases, and we hope to be able to summarize more effective and promising nano-drug diagnosis and treatment systems that aim to improve the survival of patients with advanced MBC. We describe nanoplatform-based experimental studies and clinical trials targeting the tumor and the tumor microenvironment (TME) for BCLM to obtain more targeted treatment and in the future treatment steps for patients to provide a pioneering strategy.

The proportion of patients with breast cancer and obesity is increasing. While the therapeutic landscape of breast cancer has been expanding, we lack knowledge about the potential differential efficacy of most drugs according to the body mass index (BMI). Here, we conducted a systematic review on recent clinical drug trials to document the dosing regimen of recent drugs, the reporting of BMI and the possible exclusion of patients according to BMI, other adiposity measurements and/or diabetes (leading comorbidity of obesity). We further explored whether treatment efficacy was evaluated according to BMI.

A search of Pubmed and ClinicalTrials.gov was performed to identify phase I-IV trials investigating novel systemic breast cancer treatments. Dosing regimens and exclusion based on BMI, adiposity measurements or diabetes, documentation of BMI and subgroup analyses according to BMI were assessed.

495 trials evaluating 26 different drugs were included. Most of the drugs (21/26, 81%) were given in a fixed dose independent of patient weight. BMI was an exclusion criterion in 3 out of 495 trials. Patients with diabetes, the leading comorbidity of obesity, were excluded in 67/495 trials (13.5%). Distribution of patients according to BMI was mentioned in 8% of the manuscripts, subgroup analysis was performed in 2 trials. No other measures of adiposity/body composition were mentioned in any of the trials. Retrospective analyses on the impact of BMI were performed in 6 trials.

Patient adiposity is hardly considered as most novel drug treatments are given in a fixed dose. BMI is generally not reported in recent trials and few secondary analyses are performed. Given the prevalence of patients with obesity and the impact obesity can have on pharmacokinetics and cancer biology, more attention should be given by investigators and study sponsors to reporting patient's BMI and evaluating its impact on treatment efficacy and toxicity.

Endocrine therapy (ET) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the first-line standard treatment for most patients with hormone receptor-positive (HR+) and human epidermal growth receptor 2-negative (HER2-) metastatic or advanced breast cancer. However, the majority of tumors response to and eventually develop resistance to CDK4/6is. The mechanisms of resistance are poorly understood, and the optimal postprogression treatment regimens and their sequences continue to evolve in the rapidly changing treatment landscape. In this review, we generally summarize the mechanisms of resistance to CDK4/6is and ET, and describe the findings from clinical trials using small molecule inhibitors, antibody-drug conjugates and immunotherapy, providing insights into how these novel strategies may reverse treatment resistance, and discussing how some have not translated into clinical benefit. Finally, we provide rational treatment strategies based on the current emerging evidence.

Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer mortality in women. As the phosphatidylinositol 3-kinase (PI3K) signaling pathway is involved in a wide range of physiological functions of cells including growth, proliferation, motility, and angiogenesis, any alteration in this axis could induce oncogenic features; therefore, numerous preclinical and clinical studies assessed agents able to inhibit the components of this pathway in BC patients. To the best of our knowledge, this is the first study that analyzed all the registered clinical trials investigating safety and efficacy of the PI3K/AKT/mTOR axis inhibitors in BC. Of note, we found that the trends of PI3K inhibitors in recent years were superior as compared with the inhibitors of either AKT or mTOR. However, most of the trials entering phase III and IV used mTOR inhibitors (majorly Everolimus) followed by PI3K inhibitors (majorly Alpelisib) leading to the FDA approval of these drugs in the BC context. Despite favorable efficacies, our analysis shows that the majority of trials are utilizing PI3K pathway inhibitors in combination with hormone therapy and chemotherapy; implying monotherapy cannot yield huge clinical benefits, at least partly, due to the activation of compensatory mechanisms. To emphasize the beneficial effects of these inhibitors in combined-modal strategies, we also reviewed recent studies which investigated the conjugation of nanocarriers with PI3K inhibitors to reduce harmful toxicities, increase the local concentration, and improve their efficacies in the context of BC therapy.

The H1047R mutation of PIK3CA is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3KαH1047R over PI3KαWT is crucial due to the role that PI3KαWT plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3KαH1047R-selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3KαH1047R with high selectivity over PI3KαWT, resulting in the discovery of compound 17. When dosed in the HCC1954 tumor model in mice, 17 provided tumor regressions and a clear pharmacodynamic response. X-ray cocrystal structures from several PI3Kα inhibitors were obtained, revealing three distinct binding modes within PI3KαH1047R including a previously reported cryptic pocket in the C-terminus of the kinase domain wherein we observe a ligand-induced interaction with Arg1047.

Most adult human cancers are solid tumors prevailing in vital organs and lead to mortality all over the globe. Genetic and epigenetic alterations in cancer genes or genes of associated signaling pathways impart the most common characteristic of malignancy, that is, uncontrolled proliferation. Unless the mechanism of action of these cells signaling pathways (involved in cell proliferation, apoptosis, metastasis, and the maintenance of the stemness of cancer stem cells and cancer microenvironment) and their physiologic alteration are extensively studied, it is challenging to understand tumorigenesis as well as develop new treatments and precision medicines. Targeted therapy is one of the most promising strategies for treating various cancers. However, cancer is an evolving disease, and most patients develop resistance to these drugs by acquired mutations or mediation of microenvironmental factors or due to tumor heterogeneity. Researchers are striving to develop novel therapeutic options like combinatorial approaches targeting multiple responsible pathways effectively. Thus, in-depth knowledge of cell signaling and its components remains a critical topic of cancer research. This chapter summarized various extensively studied pathways in solid cancer and how they are targeted for therapeutic strategies.

Alpelisib (ALP) is a potent anti-cancer drug showing promising activity against advanced breast cancers. Hence, profound understanding of its binding dynamics within the physiological system is vital. Herein, we have investigated interaction of ALP with human serum albumin (HSA) and bovine serum albumin (BSA) using spectroscopic techniques like absorption, fluorescence, time-resolved, synchronous and 3D-fluorescence, FRET, FT-IR, CD, and molecular docking studies. The intrinsic fluorescence of both BSA and HSA quenched significantly by ALP with an appreciable red shift in its emission maxima. Stern-Volmer analysis showed increase in Ksv with temperature indicating involvement of dynamic quenching process. This was further validated by no significant change in absorption spectrum of BSA and HSA (at 280 nm) upon ALP interaction, and by results of fluorescence time-resolved lifetime studies. ALP exhibited moderately strong binding affinity with BSA (of the order 106 M-1) and HSA (of the order 105 M-1), and the major forces accountable for stabilizing the interactions are hydrophobic forces. Competitive drug binding experiments and molecular docking suggested that ALP binds to site I in subdomain IIA of BSA and HSA. The Förster distance r was found to be less than 8 nm and 0.5 Ro < r < 1.5 Ro which suggests possible energy transfer between donors BSA/HSA and acceptor ALP. Synchronous and 3D-fluoresecnce, FT-IR and CD studies indicated that ALP induces conformational changes of BSA and HSA upon interaction.Communicated by Ramaswamy H. Sarma.

The MAPK and PI3K pathways are involved in cancer growth and survival; however, the clinical efficacy of single inhibitors of each pathway is limited or transient owing to resistance mechanisms, such as feedback signaling and/or reexpression of receptor-type tyrosine kinases (RTK). This study identified a potent and novel kinase inhibitor, TAS0612, and characterized its properties. We found that TAS0612 is a potent, orally available compound that can inhibit p90RSK (RSK), AKT, and p70S6K (S6K) as a single agent and showed a strong correlation with the growth inhibition of cancer cells with PTEN loss or mutations, regardless of the presence of KRAS and BRAF mutations. Additional RSK inhibitory activity may differentiate the sensitivity profile of TAS0612 from that of signaling inhibitors that target only the PI3K pathway. Moreover, TAS0612 demonstrated broad-spectrum activity against tumor models wherein inhibition of MAPK or PI3K pathways was insufficient to exert antitumor effects. TAS0612 exhibited a stronger growth-inhibitory activity against the cancer cell lines and tumor models with dysregulated signaling with the genetic abnormalities described above than treatment with inhibitors against AKT, PI3K, MEK, BRAF, and EGFR/HER2. In addition, TAS0612 demonstrated the persistence of blockade of downstream growth and antiapoptotic signals, despite activation of upstream effectors in the signaling pathway and FoxO-dependent reexpression of HER3. In conclusion, TAS0612 with RSK/AKT/S6K inhibitory activity may provide a novel therapeutic strategy for patients with cancer to improve clinical responses and overcome resistance mechanisms.

"Targeted therapy" or "precision medicine" is a therapeutic strategy launched over two decades ago. It relies on drugs that inhibit key molecular mechanisms/pathways or genetic/epigenetic alterations that promote different cancer hallmarks. Many clinical trials, sponsored by multinational drug companies, have been carried out. During this time, research has increasingly uncovered the complexity of advanced breast cancer disease. Despite high expectations, patients have seen limited benefits from these clinical trials. Commonly, only a minority of trials are successful, and the few approved drugs are costly. The spread of this expensive therapeutic strategy has constrained the resources available for alternative research. Meanwhile, due to the high cost/benefit ratio, other therapeutic strategies have been proposed by researchers over time, though they are often not pursued due to a focus on precision medicine. Notable among these are drug repurposing and counteracting micrometastatic disease. The former provides an obvious answer to expensive targeted therapies, while the latter represents a new field to which efforts have recently been devoted, offering a "way beyond" the current research.

Although approximately 70% of bladder cancers are noninvasive and have high recurrence rates, early-stage disease is understudied. The lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. Although mutations in PIK3CA are frequent in human bladder cancer, an in vivo model for understanding their contribution to bladder tumorigenesis is unavailable. Therefore, a Upk2-Cre/Pik3caH1047R mouse model expressing one or two R26-Pik3caH1047R alleles in a urothelium-specific manner was generated. Pik3caH1047R functionality was confirmed by quantifying Akt phosphorylation, and mice were characterized by assessing urothelial thickness, nuclear atypia, and expression of luminal and basal markers at 6 and 12 months of age. While at 6 months, Pik3caH1047R mice developed increased urothelial thickness and nuclear atypia, progressive disease was not observed at 12 months. Immunohistochemistry showed urothelium maintained luminal differentiation characterized by high forkhead box A1 (Foxa1) and peroxisome proliferator-activated receptor γ expression. Surprisingly, Pik3caH1047R mice subjected to low-dose carcinogen exposure [N-butyl-N-(4-hydroxybutyl)nitrosamine] exhibited no significant differences after exposure relative to mice without exposure. Furthermore, single-sample gene set enrichment analysis of invasive human tumors showed those with mutant PIK3CA did not exhibit significantly increased phosphatidylinositol 3-kinase/AKT pathway activity compared with wild-type PIK3CA tumors. Overall, these data suggest that Pik3caH1047R can elicit early tumorigenic changes in the urothelium, but progression to invasion may require additional genetic alterations.

Phosphoinositide 3-kinases (PI3Ks) generate lipids that control multitudinous intracellular cell signaling events which participate in cell survival and proliferation. In addition, PI3K signaling also contributes to metabolism, immunity, angiogenesis and cardiovascular homeostasis, and many diseases. The diverse actions of PI3K stem from the existence of their various isoforms and a variety of protein effectors. Hence, PI3K isoform-specific inhibitors have already achieved a wonderful effect on treating cancer. Herein, we summarize the molecular mechanism of PI3K inhibitors in preventing the permeability of vessels and neovascularization. Additionally, we briefly illustrate how PI3K signaling modulates blood vessel growth and discuss the different roles that PI3K isoforms play in angiogenesis.

PIK3CA is the second most mutated gene in cancer leading to aberrant PI3K/AKT/mTOR signaling and increased translation, proliferation, and survival. Some 4%-25% of gastric cancers display activating PIK3CA mutations, including 80% of Epstein-Barr virus-associated GCs. Small molecules, including pan-PI3K and dual PI3K/mTOR inhibitors, have shown moderate success clinically, due to broad on-target/off-tissue effects. Thus, isoform-specific and mutant selective inhibitors have been of significant interest. However, drug resistance is a problem and has affected success of new drugs. There has been a concerted effort to define mechanisms of resistance and identify potent combinations in many tumor types, though gastric cancer is comparatively understudied. In this study, we identified modulators of the response to the PI3Kα-specific inhibitor, BYL719, in PIK3CA-mutant GCs. We found that loss of NEDD9 or inhibition of BCL-XL conferred hypersensitivity to BYL719, through increased cell-cycle arrest and cell death, respectively. In addition, we discovered that loss of CBFB conferred resistance to BYL719. CBFB loss led to upregulation of the protein kinase PIM1, which can phosphorylate and activate several overlapping downstream substrates as AKT thereby maintaining pathway activity in the presence of PI3Kα inhibition. The addition of a pan-PIM inhibitor re-sensitized resistant cells to BYL719. Our data provide clear mechanistic insights into PI3Kα inhibitor response in PIK3CA-mutant gastric tumors and can inform future work as mutant-selective inhibitors are in development for diverse tumor types.

Loss of either NEDD9 or BCL-XL confers hypersensitivity to PI3K-alpha inhibition whereas loss of CBFB confers resistance through a CBFB/PIM1 signaling axis.

The PI3K/AKT/mTOR signaling pathway is well known to be involved in cell growth, proliferation, metabolism and other cellular physiological processes. Abnormal activation of this pathway is closely related to tumorigenesis and metastasis. As the starting node of the pathway, PI3K is known to contain 4 isoforms, including PI3Kα, a heterodimer composed of the catalytic subunit p110α and the regulatory subunit p85. PIK3CA, which encodes p110α, is frequently mutated in cancer, especially breast cancer. Abnormal activation of PI3Kα promotes cancer cell proliferation, migration, invasion, and angiogenesis; therefore, PI3Kα has become a key target for the development of anticancer drugs. The hinge region and the region of the mutation site in the PI3Kα protein are important for designing PI3Kα-specific inhibitors. As the group shared by the most PI3Kα-specific inhibitors reported thus far, carboxamide can produce hydrogen bonds with Gln859 and Ser854. Gln859 is specific to the p110α protein in producing hydrogen bond interactions with PI3Kα-specific inhibitors and this is a key point for designing PI3Kα inhibitors. To date, alpelisib is the only PI3Kα inhibitor approved for the treatment of breast cancer. Several other PI3Kα inhibitors are under evaluation in clinical trials. In this review, we briefly describe PI3Kα and its role in tumorigenesis, summarize the clinical trial results of some PI3Kα inhibitors as well as the synthetic routes of alpelisib, and finally give our proposal for the development of novel PI3Kα inhibitors for tumor therapy. HighlightsWe summarize the progress of PI3Kα and PI3Kα inhibitors in cancer from the second half of the 20th century to the present.We describe the clinical trial results of PI3Kα inhibitors as well as the synthetic routes of the only approved PI3Kα inhibitor alpelisib.Crystal structure of alpelisib bound to the PI3Kα receptor binding domain.This review gives proposal for the development of novel PI3Kα inhibitors and will serve as a complementary summary to other reviews in the research field of PI3K inhibitors.Communicated by Ramaswamy H. Sarma.

The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

The tumor microenvironment is overwhelmingly dictated by macrophages, intimately affiliated with tumors, exercising pivotal roles in multiple processes, including angiogenesis, extracellular matrix reconfiguration, cellular proliferation, metastasis, and immunosuppression. They further exhibit resilience to chemotherapy and immunotherapy via meticulous checkpoint blockades. When appropriately stimulated, macrophages can morph into a potent bidirectional component of the immune system, engulfing malignant cells and annihilating them with cytotoxic substances, thus rendering them intriguing candidates for therapeutic targets. As myelomonocytic cells relentlessly amass within tumor tissues, macrophages rise as prime contenders for cell therapy upon the development of chimeric antigen receptor effector cells. Given the significant incidence of macrophage infiltration correlated with an unfavorable prognosis and heightened resistance to chemotherapy in solid tumors, we delve into the intricate role of macrophages in cancer propagation and their promising potential in confronting four formidable cancer variants-namely, melanoma, colon, glioma, and breast cancers.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC) with an aggressive clinical nature and poor prognosis. With novel targeted therapeutics being developed, new ways to effectively treat PSC are emerging. In this study, we analyze demographics, tumor characteristics, treatment modalities, and outcomes of PSC and genetic mutations in PSC. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database were reviewed to analyze cases of pulmonary sarcomatoid carcinoma from 2000 to 2018. The molecular data with the most common mutations in PSC were extracted from the Catalogue Of Somatic Mutations in Cancer (COSMIC) database. Results: A total of 5259 patients with PSC were identified. Most patients were between 70 and 79 years of age (32.2%), male (59.1%), and Caucasian (83.7%). The male-to-female ratio was 1.45:1. Most tumors were between 1 and 7 cm in size (69.4%) and poorly differentiated (grade III) (72.9%). The overall 5-year survival was 15.6% (95% confidence interval (95% CI) = 14.4-16.9)), and the cause-specific 5-year survival was 19.7% (95% CI = 18.3-21.1). The five-year survival for those treated with each modality were as follows: chemotherapy, 19.9% (95% CI = 17.7-22.2); surgery, 41.7% (95% CI = 38.9-44.6); radiation, 19.1% (95% CI = 15.1-23.5); and multimodality therapy (surgery and chemoradiation), 24.8% (95% CI = 17.6-32.7). On multivariable analysis, age, male gender, distant stage, tumor size, bone metastasis, brain metastasis, and liver metastasis were associated with increased mortality, and chemotherapy and surgery were associated with reduced mortality (p < 0.001). The best survival outcomes were achieved with surgery. The most common mutations identified in COSMIC data were TP53 31%, ARID1A 23%, NF1 17%, SMARCA4 16%, and KMT2D 9%. Conclusions: PSC is a rare and aggressive subtype of NSCLC, usually affecting Caucasian males between 70 and 79. Male gender, older age, and distant spread were associated with poor clinical outcomes. Treatment with surgery was associated with better survival outcomes.

Activating mutations in the PIK3CA gene, causing phosphoinositide 3-kinase (PI3K) hyperactivation, are rare causes of hypoglycemia. We report the novel use of alpelisib (a PI3K inhibitor) for the treatment of hypoketotic, hypoinsulinemic hypoglycemia in 2 children with PIK3CA-related overgrowth spectrum (PROS). Patient 1 was a 7-month-old girl who presented with a hypoglycemic seizure. Despite nutritional management including continuous feeds, she continued to have frequent hypoglycemia. At age 2.8 years, alpelisib was started at 50 mg daily and titrated to 100 mg daily. She was weaned off nocturnal continuous feeds by 8 months. She developed colitis when the alpelisib dose was increased to 125 mg, but this resolved with a dose decrease and medical management. At age 5.3 years, she was doing well with rare hypoglycemia. Her accelerated growth stabilized. Patient 2 was a 3-year-old boy who developed hypoglycemia in early infancy. Alpelisib 50 mg daily was started due to recurrent hypoglycemia despite nutritional management. He came off continuous feeds after 4 months, with decreased hypoglycemia frequency. At age 4.5 years, he had not experienced side effects from treatment. In conclusion, alpelisib appears to be effective in decreasing PROS-related hypoglycemia frequency and severity and should be considered for refractory hypoglycemia in this condition.

The phosphoinositide 3-kinase (PI3K) signaling pathway is well-known for its important role in cancer growth, proliferation and migration. The activation of PI3K pathway is always connected with endocrine resistance and poor prognosis in cancers. Alpelisib, a selective inhibitor of PI3K, has been demonstrated to be effective in combination with endocrine therapy in HR+ PIK3CA-mutated advanced breast cancer in preclinical and clinical trials. Recently, the synergistic effects of alpelisib combined with targeted agents have been widely reported in PIK3CA-mutated cancer cells, such as breast, head and neck squamous cell carcinoma (HNSCC), cervical, liver, pancreatic and lung cancer. However, previous reviews mainly focused on the pharmacological activities of alpelisib in breast cancer. The synergistic therapeutic potential of alpelisib in other cancers has not yet been well reviewed. In this review, an extensive study of related literatures (published until December 20, 2022) regarding the anti-cancer functions and synergistic effects of alpelisib was carried out through the databases. Useful information was extracted. We summarized the preclinical and clinical studies of alpelisib in combination with targeted anti-cancer agents in cancer treatment (excluding breast cancer). The combinations of alpelisib and other targeted agents significantly improved the therapeutic efficacy both in preclinical and clinical studies. Unfortunately, synergistic therapies still could not effectively avoid the possible toxicities and adverse events during treatment. Finally, some prospects for the combination studies in cancer treatment were provided in the paper. Taken together, this review provided valuable information for alpelisib in preclinical and clinical applications.

Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype of breast cancer, and current treatments are only partially effective in disease control. More effective combination approaches are needed to improve the survival of TNBC patients. Eribulin mesylate, a non-taxane microtubule dynamics inhibitor, is approved by the U.S. Food and Drug Administration to treat metastatic breast cancer after at least two previous chemotherapeutic regimens. However, eribulin as a single agent has limited therapeutic efficacy against TNBC.

High-throughput kinome library RNAi screening, Ingenuity Pathway Analysis, and STRING analysis were performed to identify target kinases for combination with eribulin. The identified combinations were validated using in vivo and ex vivo proliferation assays.

We identified 135 potential kinase targets whose inhibition enhanced the antiproliferation effect of eribulin in TNBC cells, with the PI3K/Akt/mTOR and the MAPK/JNK pathways emerging as the top candidates. Indeed, copanlisib (pan-class I PI3K inhibitor), everolimus (mTOR inhibitor), trametinib (MEK inhibitor), and JNK-IN-8 (pan-JNK inhibitor) produced strong synergistic antiproliferative effects when combined with eribulin, and the PI3K and mTOR inhibitors had the most potent effects in vitro.

Our data suggest a new strategy of combining eribulin with PI3K or mTOR inhibitors to treat TNBC.

The frequent activation of the PI3K/AKT/mTOR pathway and its crucial role in estrogen receptor-positive (ER+) breast cancer tumorigenesis and drug resistance has made it a highly attractive therapeutic target in this breast cancer subtype. Consequently, the number of new inhibitors in clinical development targeting this pathway has drastically increased. Among these, the PIK3CA isoform-specific inhibitor alpelisib and the pan-AKT inhibitor capivasertib were recently approved in combination with the estrogen receptor degrader fulvestrant for the treatment of ER+ advanced breast cancer after progression on an aromatase inhibitor. Nevertheless, the clinical development of multiple inhibitors of the PI3K/AKT/mTOR pathway, in parallel with the incorporation of CDK4/6 inhibitors into the standard of care treatment in ER+ advanced breast cancer, has led to a multitude of available therapeutic agents and many possible combined strategies which complicate personalizing treatment. Here, we review the role of the PI3K/AKT/mTOR pathway in ER+ advanced breast cancer, highlighting the genomic contexts in which the various inhibitors of this pathway may have superior activity. We also discuss selected trials with agents targeting the PI3K/AKT/mTOR and related pathways as well as the rationale supporting the clinical development of triple combination therapy targeting ER, CDK4/6 and PI3K/AKT/mTOR in ER+ advanced breast cancer.