pictilisib (GDC-0941) / Roche - LARVOL DELTA

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

mTORC1 Dependency is a Therapeutic Vulnerability in KRAS-Mutant Non-Small Cell Lung Cancer (IASLC-WCLC 2024) - "RMC-7797 was evaluated both as monotherapy and in combination with PI3K/mTOR pathway inhibitors including the new bi-steric mTORC1 kinase-selective inhibitor RMC-6272, a pan-AKT inhibitor MK-2206, and the pan-PI3K inhibitor GDC-0941. We have identified inhibition of the mTORC1 as a critical mediator of sensitivity to KRAS inhibitors in KRAS mutant-driven NSCLC. The combination of the RAS-multi inhibitor RMC-7797 and the mTORC1-selective inhibitor RMC-6272 shows broad efficacy in preclinical models in vivo. These preclinical data support the clinical evaluation of this combinatorial therapeutic strategy in patients with KRAS mutant-driven NSCLC."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • MCL1

The molecular background determines LSD1 inhibition sensitization of AML cells to gilteritinib and other kinase inhibitors (EACR 2024) - "Here, we hypothesise that the molecular background of AML determines the precise combinations of epigenetic and kinase targeting drugs that more effectively disrupt the dependencies that drive AML.Material and Methods Mega-erythroid (HEL, KMOE2 and CMK) and monocytic (MV4-11, P31 and NOMO1) AML cells were treated with the LSD1 inhibitor (LSD1i) GSK-2879552 for five days, followed by treatments with inhibitors of FLT3 (midostaurin and gilteritinib), MEK (trametinib), and PI3K (alpelisib, TGX-221, duvelisib, idelalisib and pictilisib aimed for α, β, δ/ɣ, δ and all isoforms) for three days. LSD1i reduced histone H3K79 methylation only in P31 cells and inhibitors of DOT1L, the enzyme that methylates H3K79, sensitized P31 cells to MEKi but not HEL cells to PI3Ki. These data suggest that the LSD1i induced sensitization to MEKi in P31 cells involves DOT1L, while the sensitization to PI3Kis in HEL cells may involve the lost of erythroid differentiation and energy metabolism..."

Acute Myelogenous Leukemia • DOT1L • FLT3 • PIK3CD

SARS-CoV-2-induced phosphorylation and its pharmacotherapy backed by artificial intelligence and machine learning. (PubMed, Future Sci OA) - "Promising therapeutic candidates, including gilteritinib, pictilisib, sorafenib, RO5126766 and omipalisib, were identified. This research offers insights into SARS-CoV-2 pathogenicity, highlighting potential treatments and harmful variants in viral proteins."

Journal • Machine learning • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

GT0486, a novel mTORC1/2 dual inhibitor, exhibits synergistic antitumor efficacy in combination with BTK inhibitors (AACR 2024) - "Compared with other mTOR inhibitors (GDC-0349, AZD-2014, Rapamycin, GDC-0941, and CC-223), GT0486 exhibits the stronger inhibitory activity on human tumor cells, such as U87(glioma), PC-3(prostate cancer), MDA-MB-468(breast cancer) and Huh-7(liver cancer)...High synergistic effects were observed with GT0486 in combination with BTK inhibitors, including Acalabrutinib, Ibrutinib, Zanubrutinib and Orelabrutinib in the BTKi sensitive TMD8 cells...These results demonstrate that GT0486 is a promising dual mTOR1/2 inhibitor, which is currently undergoing clinical phase I study in China for the treatment of solid tumors. Strong synergistic effects observed with GT0486 in combination with BTKi in this study might open a way for a novel treatment strategy in clinical trials."

Clinical • Combination therapy • Brain Cancer • Breast Cancer • CNS Tumor • Gastrointestinal Cancer • Genito-urinary Cancer • Glioma • Hematological Malignancies • Liver Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor • EIF4EBP1

RTK signaling and WT RAS activity as vulnerabilities in tumors with acquired resistance to GDP-state selective KRASG12C inhibitors in preclinical models (AACR 2024) - "Background: KRASG12C-GDP Inhibitors such as sotorasib and adagrasib have demonstrated clinical benefit in lung cancer patients harboring an oncogenic KRASG12C mutation. These data suggest that in KRASG12C-GDP inhibitor-resistant models RTK activation maintains MAPK dependency and in the case of one model, PI3K signaling. Consistent with these mechanisms, RMC-7977 as a single agent or in combination with pictilisib drove significant tumor regressions in these models. These preclinical results indicate RASMULTI-GTP inhibition alone or combination with PI3K inhibition has the potential to address KRASG12C-GDP inhibitor resistance."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • ERBB3 • HER-2 • KRAS

Neuron-derived neurotensin promotes pancreatic cancer invasiveness and gemcitabine resistance via the NTSR1/Akt pathway. (PubMed, Am J Cancer Res) - "GDC-0941, a clinically approved PI3K inhibitor, counteracted NTS-induced effects in vitro. NTS boosted gemcitabine resistance via NTSR1 in pancreatic cancer. Our results suggest that neural cell-secreted NTS plays an important role in promoting PDAC."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • NTS

Simultaneous inhibition of PI3K and PAK in preclinical models of neurofibromatosis type 2-related schwannomatosis. (PubMed, Oncogene) - "We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis."

Journal • Preclinical • Brain Cancer • Fibrosis • Genetic Disorders • Neurofibromatosis • Oncology • Solid Tumor • NF2

Fluoxetine exerts anti-inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release. (PubMed, Exp Dermatol) - "Importantly, the PI3K-inhibitor GDC0941 fully mimicked the effects of fluoxetine (Q-PCR, ELISA). Collectively, our findings demonstrate that fluoxetine exerts potent anti-inflammatory effects, and suppresses the release of the endogenous itch mediator endothelins in human keratinocytes, most likely via interfering with the PI3K pathway. Thus, clinical studies are encouraged to explore whether the currently reported beneficial effects translate in vivo following its topical administration in inflammatory and pruritic dermatoses."

Journal • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease