pictilisib (GDC-0941) / Roche - LARVOL DELTA

Tumor Microenvironmental NRG1 Drives Resistance to PI3K Pathway Inhibition in Prostate Cancer (SUO 2025) - "Cells were treated with PI3K pathway inhibitors (GDC-0941, Capivasertib, Sapanisertib) alone and in combination with enzalutamide, an androgen receptor inhibitor...In 22RV1 cell line xenografts, combination therapy with seribantumab, enzalutamide, and pictilisib significantly suppressed tumor growth compared to enzalutamide and pictilisib alone ( Figure 1D )... The TME-derived secretome plays a critical role in modulating resistance to targeted therapies in prostate cancer. NRG1 in the PCa TME, activates HER3 signaling and promotes resistance to both AR and PI3K pathway inhibitors. Targeting HER3 in combination with PI3K inhibitors represents a promising therapeutic strategy to overcome NRG1-mediated resistance mechanisms in advanced prostate cancer."

Biomarker • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • NRG1

Novel benzoxazole-based hybrids as multi-target inhibitors of aromatase, EGFR, and PI3K with potential anti-breast cancer activity. (PubMed, Bioorg Med Chem) - "MTT assay showed that 6 and 9b were 4.5 and 2 times more potent than doxorubicin against MCF-7 cells, while 9a and 13b were 10 and 7.5 times more effective against MDA-MB-231 cells, respectively...Compound 13b exhibited comparable EGFRL858R inhibition to lapatinib and outperformed pictilisib against PI3Kα, PI3Kβ, and PI3Kδ. Compound 6 showed greater ARO inhibition than letrozole, while being slightly less potent than pictilisib against PI3Kα and PI3Kβ...Docking studies supported the in vitro enzymatic inhibition assays results. Thus, 9b and 13d are potent anti-breast cancer benzoxazoles with selective ARO and PI3kα inhibition activity, respectively, while 6, 9a, and 13b are multi-target inhibitors exhibiting other anticancer synergistic mechanisms."

Journal • Breast Cancer • Oncology • Solid Tumor • ANXA5 • BECN1 • CASP9 • EGFR • PIK3CA • PIK3CB • PIK3CD

Development of isogenic models of marginal zone lymphoma for therapeutic target discovery in TET2-deficient disease (AACR-NCI-EORTC 2025) - "Pharmacological screening in wt and mut-TET2 monoclonal cells showed that several drugs, such as pictilisib, rapamycin, romidepsin, tucidinostat, and umbralisib, were more active in mut-TET2 cells, and their targets largely agreed with what was observed at the transcriptome level.Conclusions. Further, mut-TET2 conferred increased sensitivity to the TET inhibitor TETi76 and to multiple targeted agents, particularly those targeting PI3K, MTOR, and histone deacetylases. Our findings provide novel insights into the role of mut-TET2 in lymphomagenesis and reveal potential drug-targetable pathways for lymphomas with mut-TET2."

Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Oncology • TET2

Inhibiting JNK and PI3K-Akt signaling pathways altered spontaneous network bursts and developmental trajectories of neuronal networks. (PubMed, J Neural Eng) - "This study investigates the roles of JNK and PI3K-Akt signaling in regulating spontaneous NBs dynamics and network organization in cultured neuronal networks. Approach: Using longitudinal microelectrode array (MEA) recordings from cultured cortical neurons (DIV14-49), we pharmacologically inhibited JNK (SP600125, JNK-IN-8) and PI3K-Akt (LY294002, GDC-0941) pathways. JNK signaling is crucial for maintaining early core-node functionality, whereas PI3K-Akt signaling promotes the development of mature modular architecture. Our findings enhance the understanding of how molecular signaling influences neuronal network dynamics, contributing to a broader framework for studying neurodevelopmental principles.&#xD."

Journal

Targeting the KLF5/PI3K/AKT axis as a therapeutic strategy to overcome neoadjuvant chemoresistance in colorectal cancer. (PubMed, Front Immunol) - "Through high-throughput screening, GDC-0941, a PI3K/AKT inhibitor, emerged as a promising therapeutic agent that synergistically enhanced oxaliplatin efficacy and overcame resistance in preclinical models. Targeting the KLF5/PI3K/AKT axis may enhance chemotherapy efficacy and overcome drug resistance in CRC."

Journal • Colorectal Cancer • Oncology • Solid Tumor • KLF5

Orphan Class A GPCRs Signature Predicts Prognosis and Immune Microenvironment in Gastric Cancer: GPR176 Drives Tumor Progression Through Wnt Signaling and Macrophage Polarization. (PubMed, Mediators Inflamm) - "Low-risk patients showed higher sensitivity to AZD6482, BX.795, GDC0941, and pazopanib. GPR176 also modulated the Wnt/β-catenin pathway and M2 macrophage polarization. These findings may provide new insights into the role of orphan class A GPR genes in STAD and identify GPR176 as a new therapeutic target for GC."

Journal • Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • GPR176 • GPRC6A • PR176

Identification of potential drug targets for achalasia from genetic insights: a Mendelian randomization study. (PubMed, J Cardiothorac Surg) - "This study identifies potential drug targets for the treatment of different fractions and sites of AC, and these findings provide promising clues for more effective treatment of AC and have the potential to reduce drug development costs."

Journal • Gastrointestinal Disorder • Rare Diseases • BST2 • CD14 • CDK14 • IFIT1

THE MOLECULAR BACKGROUND DETERMINES THE EXTENT BY WHICH LSD1 INHIBITORS SENSITIZE AML CELLS TO KINASE AND RAS INHIBITORS (EHA 2025) - "These cells present FLT3, NRAS and JAK2 activating mutations, respectively.Independently of FLT3 and RAS mutations, Iadademstat, sensitized 10, 8, 8 and 7 AML cell lines to gilteritinib, trametinib, pictilisib and RMC-7977, respectively...These included the phosphorylations of pNIBAN2(Ser692) and pNFIL3(Ser287)...Remarkably, gilteritinib reduced STAT5A/B phosphorylation, and iadademstat sensitised HEL cells to the JAK inhibitor ruxolitinib. In summary, the heterogeneity by which LSD1 inhibition sensitizes AML cells to FLT3, PI3K, RAS and MEK inhibitors can be rationalised by differences in how LSD1 regulates the wirings of kinase signalling networks irrespective of FLT3 and RAS mutations."

Acute Myelogenous Leukemia • FLT3 • NRAS • STAT5

AUM-302, A NOVEL TRIPLE PIM/PI3K/MTOR INHIBITOR, SYNERGIZES WITH KRAS INHIBITION AND IMPEDES THE GROWTH OF PANCREATIC DUCTAL ADENOCARCINOMA SPHEROIDS AND ORGANOIDS (DDW 2025) - "Single- and dual kinase inhibitors TP-3654, GDC-0941, and BEZ-235, and DMSO were used as controls...Finally, combinatorial assays revealed synergy between AUM-302 and the KRAS inhibitor RMC-6236 in reducing the growth of hT1 and hM1A organoids. By blocking kinase activity, AUM-302 demonstrates potent inhibitory activity in PDAC cell lines and organoids in two different 3D culture formats. Treatment with this novel triple PIM/PI3K/mTOR inhibitor may also sensitize PDAC to other therapies, such as KRAS inhibitors."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Co-alterations in PIK3CA and ARID1A lead to greater sensitivity to PI3K pathway inhibition (AACR 2025) - "Previously we have shown that patients with mutations in both genes are more sensitive to copanlisib (cop) treatment than those with just PIK3CA(PK) mutation...An enhanced response was observed with some other PI3K inhibitors, including sapanisertib (PK=0.13; PKAD=0.014; p < 0.005) everolimus (PK=0.66, PKAD=0.36; p < 0.005) and capivasertib (PK=0.85; PKAD=0.47; p < 0.05). Cancers with PK and AD alterations have enhanced efficacy to PI3K pathway inhibition, especially those inhibitors with downstream activity against AKT or MTOR. Further mechanistic and in vivo studies are warranted in addition to further clinical validation."

Colorectal Cancer • Endometrial Cancer • Oncology • Solid Tumor • ARID1A • IFNG • IL6 • PIK3CA

ITGAV is a targetable vulnerability in epithelial ovarian cancer (AACR 2025) - "Using this platform, we have identified genes that regulate integrin signaling as a major mechanism of synthetic lethality against the PI3Ki pictilisib and the AKTi capivasertib. The mechanisms underlying induction of DNA damage and cell death in response to combination treatment are currently under investigation. The ultimate goal is to bring this combination treatment approach to HGSOC patients and shed new light on mechanisms of resistance to PI3K/AKT pathway inhibitors in ovarian cancer."

Epithelial Ovarian Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

Cancer associated fibroblast dependency in a model of muscle invasive bladder cancer (AACR 2025) - "Further editing of the Pten gene resulted in a nine-fold increase in sensitivity to the kinase inhibitor ipatasertib, while a Pikc3a H1047R hotspot mutation sensitized organoids up to 2000-fold to the Pik3 inhibitor pictilisib. Our research demonstrates the importance of CAFs in bladder cancer progression. Through further examining the mechanistic interplays between CAFs and immunoregulation, we can gain a better understanding of the main drivers and potential targets in bladder tumorigenesis."

Bladder Cancer • Genito-urinary Cancer • Oncology • Skin Cancer • Solid Tumor • CAFs • CSF2 • IL6 • PTEN • RB1 • TGFB1 • TP53

Targeting ERK and PI3K signaling in pancreatic ductal adenocarcinoma (AACR 2025) - "Using SCH772984 (an ERK 1/2 inhibitor) and pictilisib (a class I PI3K inhibitor), we evaluated their combined effects on human PDAC cell lines (MIA PaCa-2 and PANC-1) and a patient-derived xenograft (PDX) cell line. Additionally, preclinical testing in animal models will provide critical insights into the therapeutic potential of this combination. This approach represents a promising avenue for improving PDAC treatment outcomes and addressing unmet needs in this aggressive disease."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Assessment of lncRNA biomarkers based on NETs for prognosis and therapeutic response in ovarian cancer. (PubMed, Sci Rep) - "We also predicted IC50 values for chemotherapeutic drugs (bexarotene, bicalutamide, embelin, GDC0941, and thapsigargin) in high- and low-risk groups, finding higher IC50 values in low-risk patients. The risk model's robustness was validated using OC cells, tissues, and clinical datas."

Biomarker • Journal • Tumor mutational burden • Oncology • Ovarian Cancer • Solid Tumor • GAS5 • GBP1 • LINC02362 • TMB

Determining the role of the tumor microenvironment secretome on response to phosphoinositide 3-kinase pathway inhibition in prostate cancer (AUA 2025) - "GFP-labeled LNCap and PC3 cells, both PTEN-loss PCa cell lines, were plated in 384-well plates and treated with cytokine and 1 µM PI3Ki GDC-0941... Screening of a library of recombinant secreted microenvironmental proteins revealed NRG1 as a mediator of resistance to PI3K inhibition that is expressed in the TME of prostate cancer, which may in part contribute to the lack of clinical success for PI3Ki in PCa thus far. Future work will involve mechanistic exploration and to determine whether NRG1-mediated resistance represents a therapeutic opportunity in advanced PCa."

Biomarker • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Urology • NRG1 • PTEN

In vivo validation of the palmitoylation cycle as a therapeutic target in NRAS -mutant cancer. (PubMed, bioRxiv) - "We show that ABD778, a potent and selective ABHD17 inhibitor with in vivo activity, selectively reduces the growth of NRAS -mutant AML cells in vitro and is synergistic with the allosteric MEK inhibitor PD0325901 (PD901) 7,8...ABD778 augmented the anti-leukemia activity of the pan-PI3 kinase inhibitor pictilisib 9 , the K/N-Ras G12C inhibitor sotorasib 10 , and the FLT3 inhibitor gilteritinib 11 . Co-treatment with ABD778 and gilteritinib restored drug sensitivity in a patient-derived xenograft model of adaptive resistance to FLT3 inhibition. These data validate the palmitoylation cycle as a promising therapeutic target in AML and support exploring it in other NRAS -mutant cancers."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • FLT3 • NRAS

Thienopyrimidine: A promising scaffold in the development of kinase inhibitors with anticancer activities. (PubMed, Bioorg Med Chem) - "Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents. This article reviews the discovery, activity, and structure-activity relationships of antitumor kinase inhibitors based on the thienopyrimidine scaffold, and partially discusses the binding modes between thienopyrimidine derivatives and their kinase targets. By elucidating the application of thienopyrimidine derivatives as anticancer kinase inhibitors, this review aims to provide new perspectives for the development of more effective and novel kinase inhibitors."

Journal • Review • Oncology

Exploring the antiproliferative and proapoptotic activities of new pyridopyrimidine derivatives and their analogs. (PubMed, Bioorg Med Chem) - "Notably, the antitumor potency of compound 9e surpassed that of Pictilisib, inducing G2-M phase cell cycle arrest and initiating apoptosis through the intrinsic apoptotic pathway. Molecular docking studies further indicated that compound 9e binds to PI3Kα in a similar fashion to the co-crystallized ligand. Moreover, compound 9e exhibited favorable drug-like properties, including compliance with Lipinski's rule and Veber's rule, good solubility, acceptable TPSA, and high gastrointestinal absorption reinforcing its potential as a highly effective anticancer agent."

Journal • Breast Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor

Evaluation of breast cancer stem cell gene expression signatures in single-cell RNA sequencing (scRNAseq) data from the OPPORTUNE and FELINE trials, and the association with treatment resistance laparib-induced early dynamics of tumor immune microenvironment. (SABCS 2024) - " Single-cell RNAseq datasets from two clinical trials were interrogated – OPPORTUNE, a window-of-opportunity trial evaluating anastrozole vs anastrozole plus pictilisib (PI3K inhibitor) in 75 patients with ER+ HER2- early breast cancer, and FELINE, a neoadjuvant trial which compared letrozole plus placebo with letrozole plus ribociclib (CDK4/6 inhibitor) in 120 patients with ER+ HER2- early breast cancer. The use of stemness gene expression signatures in scRNAseq data is a feasible method to assess changes in putative CSC fraction with treatment in breast cancer. Increased stemness scores were associated with more aggressive subtypes and resistance to treatment."

Cancer stem • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA

Develop a Novel Signature to Predict the Survival and Affect the Immune Microenvironment of Osteosarcoma Patients: Anoikis-Related Genes. (PubMed, J Immunol Res) - "Notably, our study identified eight drugs-Bortezomib, Midostaurin, CHIR.99021, JNK.Inhibitor.VIII, Lenalidomide, Sunitinib, GDC0941, and GW.441756-as exhibiting sensitivity toward OS. The outcomes of this investigation present an opportunity to predict the survival outcomes among individuals diagnosed with OS. Furthermore, these findings hold promise for progressing research endeavors focused on prognostic evaluation and therapeutic interventions pertaining to this particular ailment."

Biomarker • Journal • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor • CD200R1 • CD36 • CD8 • CDC37 • COL13A1 • HAVCR2 • HSP90AB1 • LAIR1 • MMP3 • PIP5K1C • SCARB1 • TNFRSF1A

PIPA: Combination of PI3 Kinase Inhibitors and PAlbociclib (clinicaltrials.gov) - P1 | N=79 | Completed | Sponsor: Royal Marsden NHS Foundation Trust | Unknown status ➔ Completed

Combination therapy • Trial completion • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AKT1S1 • ER • GSK3B • HER-2 • KRAS • PIK3CA • PTH2R

RRAS and RRAS2 Mutations Are Oncogenic Drivers in Lung Cancer and are Sensitive to the Pan-RAS Inhibitor RMC-6236 (IASLC-WCLC 2024) - P1 | "ERK1/2 (ulixertinib and SCH772984), MEK1/2 (binimetinib), and PI3K (pictilisib) inhibitors inhibited growth of RRAS Q87L or RRAS2 Q72L cells more potently than cells expressing wildtype proteins. Oncogenic R RAS/RRAS2 mutations were detected in LUAD at a rate similar to some other well-characterized lung cancer drivers, such as HRAS/NRAS hotspot mutations or NRG1 fusions. Our study supports the inclusion of RRAS /RRAS2 into routine molecular diagnostic protocols for precision oncology and clinical development of pan-RAS inhibitors, such as RMC-6236, for patients with these driver mutations in order to fully realize the potential benefit of RAS-targeted therapies."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HRAS • KRAS • MAP2K1 • NRAS • NRG1 • RRAS2 • SPRY2

A NRAS mRNA G-quadruplex structure-targeting small-molecule ligand reactivating DNA damage response in human cancer cells for combination therapy with clinical PI3K inhibitors. (PubMed, Int J Biol Macromol) - "Moreover, combination therapy with NARS mRNA G4-targeting ligands and clinical PI3K inhibitors for cancer cells inhibition treatment is unexplored, and we demonstrated that B3C combining with PI3Ki (pictilisib (GDC-0941)) showed potent antiproliferation activity against HeLa cells (IC50 = 1.03 μM (combined with 10 μM PI3Ki) and 0.42 μM (combined with 20 μM PI3Ki)) and exhibited strong synergistic effects in inhibiting cell proliferation. This study provides new insights into drug discovery against RAS-driven cancers using this conceptually new combination therapy strategy."

Combination therapy • Journal • CNS Tumor • Gene Therapies • Neuroblastoma • Oncology • Solid Tumor • NRAS

MG-132 activates sodium palmitate-induced autophagy in human vascular smooth muscle cells and inhibits senescence via the PI3K/AKT/mTOR axis. (PubMed, Lipids Health Dis) - "MG-132 activates autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby inhibiting palmitate-induced proliferation, migration, and oxidative stress in vascular smooth muscle cells and suppressing their senescence."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • BECN1

Overcoming Resistance in Cancer Therapy: Computational Exploration of PIK3CA Mutations, Unveiling Novel Non-Toxic Inhibitors, and Molecular Insights Into Targeting PI3Kα. (PubMed, Bioinform Biol Insights) - "This analysis revealed Lig5's exceptional performance, exhibiting superior affinity and specificity compared to established reference inhibitors such as pictilisib...Furthermore, molecular dynamics simulations provided valuable insights into Lig5's stability and its interactions with PI3 K over 100 ns. These simulations supported Lig5's potential as a versatile inhibitor capable of effectively targeting various mutational profiles of PI3 K, thereby mitigating issues related to resistance and toxicity commonly associated with current inhibitors."

Journal • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA