pictilisib (GDC-0941) / Roche - LARVOL DELTA

CREB1 and GSK3 Isoforms as Potential Adaptive Signaling Nodes in PI3K/Akt/mTOR Inhibitor Treated Philadelphia Chromosome-Positive B-ALL. (PubMed, Int J Mol Sci) - "Experimentally, phospho-kinase arrays profiled 39 kinase phosphorylation sites in Ph+ B-ALL cells (SUPB-15) treated with PI3K/Akt/mTOR inhibitors (Rapamycin, GDC-0941, GSK690693, Perifosine). These findings position p-CREB and p-GSK-3α/β as candidate biomarkers, highlighting the value of phospho-proteomics over transcriptomics alone in capturing pathway activation. Multi-omics integration may prove essential for overcoming adaptive resistance in ALL patients."

Journal • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR • CREB1

ADAM17-Driven NKG2D Ligand Shedding Defines a Leukemia-Intrinsic Immune Evasion Program That Predicts Venetoclax Resistance and Reveals MEK and PI3K as Therapeutic Vulnerabilities in AML (SOHO 2026) - "Drug vulnerability mapping identified MEK inhibitors (trametinib, selumetinib), the HDAC inhibitor panobinostat, and PI3K/AKT/mTOR inhibitors (GDC-0941, MK-2206, and INK-128) as selectively active in NK-high AML (all FDR <0.001). An ADAM17-centered NK immune evasion score identifies venetoclax-resistant AML across two independent cohorts and associates with a survival disadvantage equivalent to an 88% increase in hazard per SD of score. This phenotype is consistent with BCL2 independence and engagement of compensatory MAPK and PI3K survival signaling, nominating MEK and PI3K inhibitors as biologically therapeutic alternatives for refractory patients. Prospective biomarker-stratified trials are required before clinical implementation of this scoring approach."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • ADAM17 • BCL2 • HLA-E • NKG2D • SMAD3 • TGFB1 • TIMP3 • ULBP1 • ULBP2

Age-Associated YBX1 Phosphorylation Regulates the Keratinocyte Senescence-Associated Secretory Phenotype Through Translational Control. (PubMed, Cells) - "Moreover, conditioned medium from PI-103- or GDC-0941-treated cells sufficiently decreased senescence in recipient cells, consistent with a paracrine, secretome-mediated effect. Together, these findings support an association between YBX1 phosphorylation and SASP chemokine output in aging human keratinocytes and nominate YBX1-directed modulation as a candidate strategy for selectively attenuating senescence-associated secretory phenotypes in intrinsic skin aging."

Journal • CXCL1 • CXCL8 • YBX1

Thieno[3,2-d]pyrimidines in Anticancer Drug Discovery: Recent Advances in Drug Design and Molecular Targets. (PubMed, Int J Mol Sci) - "The thieno[3,2-d]pyrimidine scaffolds have emerged as an important class of heterocycles in anticancer drug discovery, with clinically advanced drugs olmutinib and pictilisib highlighting their therapeutic potential. In addition, detailed structure-activity relationship analyses are provided to highlight the influence of heterocyclic fusion, linker optimization, hydrogen-bonding motifs, electronic effects, hydrophobic fragments, and the introduction of hybrid scaffolds on antiproliferative potency, kinase inhibition, selectivity, and multitarget activity. In addition, this review demonstrates the significant potential of thieno[3,2-d]pyrimidine-based scaffolds as a privileged platform for the development of next-generation targeted anticancer agents and offers valuable guidance for future medicinal chemistry research."

Journal • Review • Oncology • EGFR

Evaluation of kinase inhibitor efficacy and cancer-associated fibroblast-organoid crosstalk in a CRISPR-edited mouse model of bladder cancer (AACR 2026) - "GM-CSF knockout organoids were generated and co-cultured with CAFs to evaluate cytokine-mediated crosstalk. Triple-mutant organoids formed tumors in immunocompromised mice and exhibited sensitivity to PI3K inhibitor treatment (pictilisib or alpelisib) vs double-mutant controls, validating our genotype-specific targeting approach. Our findings suggest GM-CSF and IL-6 critically mediate CAF-dependent tumor engraftment and targeting this cytokine axis may disrupt CAF-organoid crosstalk to inhibit tumor growth in immunocompetent models. Future studies will evaluate immune contributions and dual cytokine targeting. These findings support precision medicine combining genotype-specific kinase inhibition with microenvironment-directed therapies for BCa patients harboring mTOR pathway alterations."

Preclinical • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CAFs • IL6 • PIK3CA • RB1 • TP53

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

Interrogating PI3K to induce PD-L1 expression in oral carcinoma. (ASCO 2018) - "Correlative studies with PI3K inhibitor pictilisib and dual PI3K & mTOR inhibitor dactolisib were performed. Using small molecule modulators of PI3K signaling, we demonstrate that the PI3K pathway can play opposing roles in the induction of PD-L1 and MHC I by IFN-g in oral squamous carcinoma cells. Further studies in other epithelial cancers and clinical correlates are warranted."

IO biomarker • PD(L)-1 Biomarker • Oral Cancer

Pictilisib and nutrient stress synergize to induce methuosis via PI(4,5)P2-dependent macropinocytic dysregulation in cancer cells. (PubMed, Cell Death Dis) - "Active macropinocytic uptake is essential for methuosis, as demonstrated by suppression with EIPA and Bafilomycin A1, whereas the AKT inhibitor MK2206 has no effect, establishing that direct PI3K inhibition, rather than AKT signaling, is required. In xenograft models, dietary restriction synergizes with Pictilisib to suppress tumor growth, correlating with pronounced intratumoral vacuolization. These findings reveal that combining PI3K inhibition with nutrient restriction converts cytostatic responses into methuosis-driven cytotoxicity via PI(4,5)P2-dependent macropinocytic dysregulation, providing a rational pharmacologic-dietary strategy to enhance PI3K-targeted cancer efficacy."

Journal • Oncology • AQP1

CLIP2 is a potential biomarker for platinum resistance and prognosis in ovarian cancer: a bioinformatics analysis. (PubMed, Transl Cancer Res) - "Drug sensitivity analysis revealed that high CLIP2 expression conferred resistance to platinum-based agents, topotecan, and gemcitabine, but heightened sensitivity to olaparib, cediranib, and pictilisib. Through bioinformatic analysis, this study proposes CLIP2 as a potential biomarker associated with platinum resistance and immune microenvironment patterns in ovarian cancer. These preliminary findings provide a basis for subsequent mechanistic studies and larger validation cohorts to confirm its clinical relevance in guiding immunotherapy and targeted treatment approaches."

Biomarker • IO biomarker • Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • ADORA2A • CD276 • CD48 • CD8 • ENTPD1

Integrative epidemiological and experimental evidence implicates CCNA2-associated macrophage-hepatocyte crosstalk in dimethyl phosphate exposure-associated NAFLD. (PubMed, Environ Pollut) - "Connectivity mapping combined with exploratory molecular docking analyses further identified Pictilisib as a potential therapeutic candidate for DMP-induced NAFLD, with CCNA2 predicted to function as a key downstream target...This effect was alleviated by CCNA2 silencing and restored by CCNA2 re-expression. These findings suggest that DMP may exert biological effects beyond its conventional role as an exposure biomarker and may contribute to NAFLD-related pathological processes, potentially through CCNA2-mediated macrophage-hepatocyte interactions."

Journal • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • AURKA • CCNA2 • SRSF3 • UBE2C

Tumor Microenvironmental NRG1 Drives Resistance to PI3K/AKT Pathway Inhibition in Prostate Cancer (AUA 2026) - " A library of 297 secreted factors was generated and screened for effects on response to GDC-0941, Capivasertib, or Sapanisertib ± enzalutamide in LNCaP, 22Rv1, and VCaP prostate cancer cell lines...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/HER2 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 • Urology • NRG1

Paired single cell analysis reveals chemotherapy resistance in osteosarcoma. (PubMed, Cancer Drug Resist) - " Our paired scRNA-seq approach identifies a nine-gene signature linking pre-treatment tumor biology to NAC response and outcome. The enhanced Pictilisib sensitivity in chemoresistant tumors positions PI3K blockade as a strategy meriting prospective testing in refractory osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • ADIRF • KIF1A • MIR181A1

Macrophage-related Genes were Discovered by Applying Highdimensional Weighted Gene Co-expression Network Analysis as Biomarkers for Esophageal Squamous Cell Carcinoma. (PubMed, Curr Gene Ther) - "The present findings contributed to the pathogenesis research, detection, and management of ESCC."

Biomarker • Journal • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • APOE • FTL • GPNMB • TGFBI

Integrated analysis of programmed cell death-related genes identifies CORO1A as an apoptosis-associated gene in acute myeloid leukemia. (PubMed, PeerJ) - "OncoPredict suggested higher sensitivity in the high-risk group to 5-fluorouracil, PI3K-AKT-mTOR inhibitors (afuresertib, pictilisib, taselisib, dactolisib), and the MET inhibitor savolitinib. Multi-omic integration of PCD-related genes delineates PCD-driven heterogeneity in AML and yields a robust five-gene prognostic model with therapeutic implications. CORO1A emerges as a potential apoptosis-associated oncogene that promoting AML cell survival."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2 • CD31 • CORO • CXCR3 • IL10 • ITGA4 • PECAM1 • PPBP

ELOVL1 promotes the progression of intrahepatic cholangiocarcinoma by enhancing endoplasmic reticulum stress and the PI3K/AKT/mTOR signaling pathway. (PubMed, Biol Direct) - "ELOVL1 promotes iCCA progression by regulating the PI3K/AKT/mTOR pathway and enhancing ER stress. ELOVL1 is a potential biomarker for predicting iCCA prognosis and drug response, offering new therapeutic strategies for iCCA."

Journal • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor

Zongertinib-tolerant cells enhanced sensitivity to Topo1 inhibition in Her2-positive NCSLC (AACR 2026) - "For the treatment of Her2 mutated/amplified NSCLC, the antibody-drug conjugate Trastuzumab deruxtecan, several Her2-selective inhibitors, such as zongertinib and sevabertinib, have shown beneficial efficacy in clinical settings...Drug screening revealed that zongerR cells exhibited sensitivity to the multi-tyrosine kinase inhibitor ponatinib and foretinib. Additionally, PI3K/AKT pathway inhibitors (PI3Ki) such as GDC0941 and mTOR inhibitor PP242 also markedly suppressed the survival of zongerR cells in combination with zongertinib...Currently, zongertinib and T-Dxd have been approved for Her2-positive NSCLC, whereas treatment strategies to prolong the durable response have not been well-established. Further investigations were needed, but our findings suggested that T-DXd treatment after zongertinib may be a potential therapeutic strategy in a subset of Her2-positive NSCLC."

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

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

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

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 • B Cell Lymphoma • 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

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

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

Tumor microenvironmental NRG1 activation of HER3 as a driver of resistance to PI3K pathway inhibition in prostate cancer. (ASCO-GU 2026) - "Cells were treated with PI3K pathway inhibitors (GDC-0941, Capivasertib, Sapanisertib) alone and in combination with enzalutamide, an androgen receptor inhibitor...NRG1-mediated resistance requires ligand activation and phosphorylation of the HER3 receptor as well as phosphorylation activity of HER2, and can be abrogated by treatment with anti-HER3 antibody seribantumab, knockdown with HER3 siRNA, or treatment with anti-HER2 inhibitor lapatinib. In 22RV1 cell line xenografts, combination therapy with seribantumab, enzalutamide, and pictilisib significantly suppressed tumor growth compared to enzalutamide and pictilisib alone... 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 NRG1-HER2/3 signaling in combination with PI3K inhibitors represents a promising therapeutic strategy to overcome..."

Biomarker • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ERBB3 • NRG1

AUM-302, a novel triple PIM/PI3K/mTOR inhibitor, synergizes with RAS inhibition and impedes the growth of pancreatic ductal adenocarcinoma spheroids and organoids. (PubMed, Front Pharmacol) - "Single- and dual-kinase inhibitors TP-3654, GDC-0941, BEZ-235, respectively, and DMSO were used as controls. The synergy studies were performed using AUM-302 and the RAS inhibitor RMC-6236...By blocking kinase activity, AUM-302 demonstrates potent inhibition in PDAC cell lines and organoids across two 3D culture formats. Treatment with this novel triple PIM/PI3K/mTOR inhibitor may also chemosensitize PDAC to other cancer therapies, such as RAS inhibitors."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Mechanistic Insights Into the Cooperative Interactions of PI3K/mTOR Inhibitor Pictilisib and EGCG With Human Serum Albumin: A Comprehensive Spectroscopic and Computational Study. (PubMed, Luminescence) - "These results demonstrate that HSA-mediated EGCG-Pictilisib interactions are sequence dependent, critically influencing drug distribution and bioavailability. This mechanistic insight provides a foundation for optimizing coadministration schedules in combinatorial cancer therapy."

Journal • Oncology

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