buparlisib (AN2025) / Novartis, Adlai Nortye, Nippon Kayaku - LARVOL DELTA

Development and Validation of a Rapid and Simple LC-MS/MS Method for Quantification of the Anti-Microtubule, Anti-Cancer Agent ABT-751 in Human and Mouse Plasma and Mouse Tissues. (PubMed, Biomed Chromatogr) - "Buparlisib (BKM-120) served as the internal standard. Stability concerns with ABT-751 in mouse plasma and tissue homogenate samples that were stored for more than 8 months were identified and addressed. A pilot pharmacokinetic study in mice demonstrated the applicability of this validated LC-MS/MS method."

Journal • Preclinical • Oncology

SF2523, a dual PI3K-BRD4 inhibitor, enhances KRAS (G12C) or EGFR (exon 19/21) mutant targeted inhibitors in non-small-cell lung cancer (NSCLC) (AACR 2025) - "Sotorasib and Adagrasib are a second line therapy for KRAS G12C mutant NSCLC...SF2523 IC50 in EGFR mutated NSCLC cells ranged from 90-230nM, while in KRAS mutated NSCLC cells ranged from 144-217nM versus Buparlisib plus JQ1 in the μM range...In contrast, combinations of SF2523 plus Nindetinib (VEGFR inhibitor) or Rapamycin (mTOR inhibitor) were additive in potency with EGFR and KRAS mutant NSCLC cell lines...In a SCID H2030 KRAS G12C mouse xenograft model, SF2523 at a dose of 150 mg/kg was well tolerated without weight loss with tumor growth inhibition of >60% at 6 weeks. In conclusion, our results demonstrate SF2523 is active alone and is synergistic with Osimertinib or Sotorasib in inhibiting EGFR or KRAS mutant NSCLC cell lines and is active as a single agent in a KRAS G12C mutated H2030 CDX NSCLC mouse model."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AKT1 • BRD4 • EGFR • KRAS • MYC • PIK3CA • PTEN

NF1 mutations in lung adenocarcinoma preclinical models and potential targeted therapies: The crucial role of the RAS-MAPK pathway (AACR 2025) - "No sensitivity was observed in these models when treated with the mTOR inhibitor AZD8055 or the PI3K inhibitor Buparlisib alone. We then performed in vivo pharmacological tests on the LUAD PDX: Trametinib alone and in combination with Buparlisib resulted in significant tumor volume reductions of 72% and 84%, respectively. Collectively, these findings establish a promising possible efficacy of MEK inhibitors for LUAD patients with NF1 homozygous mutation."

Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • NF1

Validation of genetically defined Oncopig hepatocellular carcinoma cell lines for in vitro evaluation of targeted therapeutic efficacy (AACR 2025) - "Therapeutic susceptibility of the established Oncopig WT, PTENKO, AXIN1KO, and ARID1KO HCC cell lines was assessed for PI3K inhibitors (GSK2636771, BAY 80-6946, and BKM120). These results validate the utility of the Oncopig HCC model for preclinical evaluation of novel targeted therapeutics in vitro. Future work demonstrating consistent results in vivo will enable the genetically defined Oncopig HCC model to be an ideal animal system to test precision medicine therapeutics prior to entry into the clinic.Therapeutic Susceptibility (Log IC50 (µM))PI3K InhibitorOncopig WT HCCOncopig AXIN1KO HCCOncopig ARID1KO HCCOncopig PTENKO HCCHuman PTEN Null CellsGSK26367711.461.170.660.07ResponsiveBAY80-694611.55.64.52.38ResponsiveBKM1202.050.95NA2.3Non-Responsive"

Preclinical • Hepatocellular Cancer • Oncology • Solid Tumor • ARID1A • KRAS • PTEN

Advancing precision cancer medicine with patient-derived organoids: an endometrial cancer case study (AACR 2025) - "We demonstrate the potential of PDO models in cancer research. By leveraging RNAseq, ATACseq, and high-throughput drug screening, this study identified actionable targets in the VEGF and PI3K pathways and validated the synergistic effects of Cediranib and BKM120 in an endometrial cancer with complex histology and genomic profile. These findings highlight the value of PDO models as innovative tools for personalizing cancer treatment and developing effective therapies for complex endometrial malignancies."

Case study • Clinical • Endometrial Cancer • Gynecologic Cancers • Oncology • Solid Tumor • ARID1A • CTNNB1 • PIK3CA

Bioinformatics analysis of genes that confers apoptosis resistance to EGFR-PI3K co-targeting (AACR 2025) - "The purpose of the current study is to identify molecular pathways that confer resistance to EGFR and PI3-K co-targeting through RNA-Seq and bioinformatics analysis. JHU022, a cell line resistant to EGFR and PI3K co-targeting was treated with the combination of erlotinib and BKM120 ± dasatinib (Src inhibitor) or crizotinib (Met inhibitor) for 24h. SRC-Met signaling confers resistance to EGFR and PI3K co-targeting by modulating genes associated with cell cycle, DNA replication, and cellular response to DNA damage.Grant Support: R15DE032063 and P20GM103434"

Head and Neck Cancer • Oncology • Solid Tumor • EGFR

A novel class of multitarget small molecule PI3K-CDK4/6-CDK9-AURAKA/B inhibitor harnesses Warburg effect against non-small cell lung cancer (AACR 2025) - "Here, we describe how LCI139 harnesses the Warburg effect to induce synthetic lethality in NSCLC. LCI139-sensitive (NCI-H1703) and resistant (NCI-H1781) human NSCLC cells, identified from prior IC50 experiments, were treated with LCI139 (0.25 and 0.5μM) or single agent inhibitors PI3Ki (BKM120), CDK4/6i (Ribociclib), CDK9i (AZD4573), and AURKAi (Alisertib). Multitarget inhibitor, LCI139 is uniquely designed to harness the Warburg effect to induce synthetic lethality in glycolysis-reliant NSCLC by 1) inducing metabolic stress (pAMPK), 2) lowering the threshold to metabolic stress response (FoxO3 stabilization), and 3) enhancing caspase-dependent cell death non-canonical Cas8 activation."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ANXA5 • BAX • BCL2 • BCL2L11 • CDK9 • SLC2A1

Longitudinal Genomic Analysis to Fine-Tune Targeted Therapy: Results of the Phase II LOGIC 2 Trial in Patients With BRAF V600-Mutant Metastatic Melanoma. (PubMed, Clin Cancer Res) - P2 | "LOGIC 2 supports the use of encorafenib plus binimetinib for treatment naive and previously treated locally advanced unresectable or metastatic BRAF V600-mutant melanoma. However, adding a third targeted agent following disease progression did not show meaningful efficacy; further research is needed to identify other therapeutic targets to circumvent resistance."

Journal • P2 data • Melanoma • Oncology • Solid Tumor • BRAF

Enhancing KRAS G12D inhibitor sensitivity in pancreatic cancer through SHP2/PI3K pathway. (PubMed, Med Oncol) - "Our study combines MRTX1133 with the SHP2 inhibitor SHP099 or PI3K inhibitor Buparlisib, showing synergistic inhibition of pancreatic cancer cell growth and enhanced apoptosis. These combination therapies could improve clinical outcomes for patients with KRAS G12D  mutation in pancreatic cancer."

Journal • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Effect of ellagic acid on BDNF/PI3K/AKT-mediated signaling pathways in mouse models of depression. (PubMed, Iran J Basic Med Sci) - "Male BALB/C mice were divided into 5 groups; vehicle (0.1 ml/day), sertraline (5mg/kg), EA (1 mg/kg), EA+BKM120 (PI3K inhibitor), EA+MK2206 (AKT inhibitor). While inhibitory agent administrations did not affect the increase of BDNF induced by EA, MK2206 administration reversed the increase in pAKT1 observed with EA. It has shown that EA has an antidepressant-like effect in mice without changing locomotor activity, and this effect may be mediated by the BDNF-PI3K-AKT signaling pathway."

Journal • Preclinical • CNS Disorders • Depression • Mood Disorders • Psychiatry

Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines. (PubMed, Int J Oncol) - "The present study aimed to investigate the efficacy of the CDK4/6 inhibitors (CDKi) palbociclib and ribociclib, and the PI3K/Akt/mTOR pathway inhibitors (PI3Ki) gedatolisib, buparlisib and alpelisib, in suppressing cell viability of HPV‑positive and ‑negative HNSCC cell lines. Whereas PI3Ki induced apoptosis and attenuated cellular metabolism, CDKi led to cell cycle arrest. Further research should be performed to elucidate whether (a combination of) these inhibitors may be effective therapeutic agents for patients with HNSCC."

Journal • Preclinical • Eye Cancer • Head and Neck Cancer • Oncology • Retinal Disorders • Retinoblastoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ANXA5 • CCND1 • CDKN2A • PTEN

Low-Dose Perifosine, a Phase II Phospholipid Akt Inhibitor, Selectively Sensitizes Drug-Resistant ABCB1-Overexpressing Cancer Cells. (PubMed, Biomol Ther (Seoul)) - "KBV20C cancer cells (P-gp overexpression, vincristine [VIC] resistance, and GSK690693-resistance), 3...Compared with other Akt inhibitors (AZD5363, BKM120, and GSK690693), low-dose perifosine specifically sensitized P-gp-overexpressing resistant MCF-7/ADR cancer cells...Considering that perifosine has both an alkyl-phospholipid structure and is an allosteric inhibitor for membrane-localizing Akt-targeting, we examined structurally and functionally similar Akt inhibitors (miltefosine and MK-2206)...These findings could contribute to its clinical use as a first-line treatment, explicitly targeting P-gp-overexpressing resistant cancer populations in heterogeneous tumor populations. Therefore, perifosine may be valuable in delaying or reducing cancer recurrence by targeting P-gp-overexpressing drug-resistant cancer cells."

Journal • P2 data • Oncology • ABCB1

Buparlisib and Paclitaxel in Patients with Head and Neck Squamous Cell Carcinoma: Immunogenomic Biomarkers of Efficacy from the BERIL-1 Study. (PubMed, Target Oncol) - P2 | "In this immunogenomic analysis of BERIL-1, improved HRs for OS were seen in patients with tumor immune infiltration and selected oncogenic alterations, including PIK3 and NOTCH pathway activation (NCT01852292)."

Biomarker • IO biomarker • Journal • Tumor mutational burden • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • NOTCH1 • PIK3CA • TMB • TP53

Dasatinib Overcomes AML Resistance to BCL2 Inhibition By Indirectly Inhibiting MCL1: From Ex Vivo drug Sensitivity/Resistance Profiling to a Phase II Clinical Trial: A Hemato-BIO Study (ASH 2024) - P=N/A | "BH3 mimetics such as the BCL2 specific inhibitor (-inh) venetoclax (VEN) and the BCL2/BLCxL-inh navitoclax (NAV), are small molecules inducing intrinsic apoptotic cell death by inhibiting antiapoptotic proteins...We noticed a strong anticorrelation between NAV-R and sensitivity to most of the tested kinase inhibitors, including the Pi3K-inh BKM120 (Buparlisib) and Idelalisib, the JAK2-inh Ruxolitinib, the MEK-inh Trametinib, the mTOR-inh Temsirolimus, the FLT3-inh Quizartinib, and the BCR-ABL-inh Imatinib and Dasatinib (DASA). On the other hand, we did not observe any anticorrelation with the EGFR-inh erlotinib nor gefitinib...DASA may be efficient in targeting VEN-R by inhibiting MCL1. Preclinical studies based on the AML collections HEMATIO-BIO allowed us to ask clinical questions that can be addressed in early-phase clinical trial."

IO biomarker • P2 data • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCL2 • BCL2L1 • BCR • EGFR • FLT3 • JAK2 • KIT • KRAS • NPM1 • NRAS • PTPN11 • TP53

Colorectal cancer (CRC) cohort analysis of patients treated with buparlisib in a distinctive tissue-agnostic trial model for molecularly preselected tumors (ASCO-GI 2015) - Abstract #644; P2, N=18; NCT01833169; Sponsor: Novartis; "Frequently observed AEs: nausea (67%), fatigue (39%), vomiting (33%), diarrhea (33%), anxiety (28%) and decreased appetite (28%). Three patients discontinued due to AEs. At week 16: 13 patients did not meet clinical benefit criteria and 5 patients were non-evaluable. Two patients had SD at week 8."

P2 data • Colorectal Cancer • Oncology

Double/Triple Combinations of AN2025, AN0025 and Atezolizumab in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=63 | Active, not recruiting | Sponsor: Adlai Nortye Biopharma Co., Ltd. | Trial primary completion date: Sep 2024 ➔ Dec 2024

Trial primary completion date • Oncology • Solid Tumor

SLC38A5 suppresses ferroptosis through glutamine-mediated activation of the PI3K/AKT/mTOR signaling in osteosarcoma. (PubMed, J Transl Med) - "SLC38A5 promotes osteosarcoma cell proliferation, migration, and invasion via the glutamine-mediated PI3K/AKT/mTOR signaling pathway and inhibits ferroptosis. Targeting SLC38A5 and the PI3K/AKT signaling axis may provide a meaningful therapeutic strategy for the future treatment of osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • SLC38A5

Design, synthesis, and biological evaluation of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives as orally bioavailable PI3K inhibitors. (PubMed, Front Pharmacol) - "Compound 17p demonstrated comparable PI3Kα inhibitory activity (IC50: 31.8 ± 4.1 nM) to the positive control, BKM-120 (IC50: 44.6 ± 3.6 nM)...In a pharmacokinetic study, 17p was stable (T ½: 2.03 h) and showed high bioavailability (46.2%). Collectively, these results indicate that 17p could be a promising PI3K agent for cancer treatment."

Journal • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA • PIK3CB • PIK3CD • PIK3CG

Comparative efficacy & safety of buparlisib plus fulvestrant, fulvestrant plus dalpiciclib, and ribociclib plus letrozole for postmenopausal, hormone receptor-positive, and HER2-negative breast cancer. (PubMed, Clinics (Sao Paulo)) - "Dalpiciclib plus fulvestrant is effective and comparatively safe in postmenopausal women with hormone receptor-positive and HER2-negative breast cancers. Dalpiciclib, buparlisib, fulvestrant, and ribociclib cause neutropenia, severe depression, adverse gastroenterological effects, and adverse hepatological effects, respectively."

Journal • Anorexia • Breast Cancer • CNS Disorders • Constipation • Depression • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Leukopenia • Mood Disorders • Neutropenia • Oncology • Psychiatry • Solid Tumor • HER-2

Combination of genomics-based targeted therapy and standard chemotherapy in xenografts derived from patients with non-small cell lung cancer (EORTC-NCI-AACR 2024) - "We observed that trametinib (MEK inhibitor), BKM120 (Pi3K inhibitor), AZD2014 (mTORC1/2 inhibitor) and palbociclib (CDK4/6 inhibitor) increased the efficacy of each chemotherapy in SCC PDXs, in contrast to a slight improvement in ADCs. In addition, we observed high efficacy of trametinib in KRAS-, HRAS- and NRAS-mutated tumors (ADCs and SCCs), and high efficacy of lorlatinib and entrectinib in the ROS1-altered ADK PDX, in which resistant-variants are on-going establishment. In summary, we report the establishment of different PDXs that recapitulate the genomic landscape of NSCLC and allowed to investigate the anti-tumor activity of different biomarker-driven targeted therapies as compared to chemotherapies. Our results suggest that the detection of pathogenic variants by NGS should be performed in all NSCLC, and in particular in SCC, in order to offer the patient a more effective combination of chemotherapy and targeted therapy."

Clinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CDKN2A • CDKN2B • EGFR • HRAS • KRAS • MAP2K4 • NF1 • NRAS • PIK3CA • PIK3R1 • RASA1 • ROS1 • STK11

Buparlisib and ponatinib inhibit aggressiveness of cholangiocarcinoma cells via suppression of IRS1-related pathway by targeting oxidative stress resistance. (PubMed, Biomed Pharmacother) - "Additionally, the drug combination significantly diminished the expression of YAP1, the cell proliferation marker and an antioxidant regulator, and increased oxidative stress-responsive markers in the xenograft model. In conclusion, targeting oxidative stress resistance with combined buparlisib and ponatinib suppressed tumor growth and migration by repressing IRS1-related pathways and ultimately inducing oxidative damage, suggesting the potential for targeted therapy and clinical trials in CCA patients over the use of a single drug."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • IRS1 • YAP1

The combination of PI3Ki (phosphatidylinositol-3-kinase inhibitor) and MEKi (mitogen-activated protein kinase inhibitor) as a promising treatment option for melanoma patients with NRAS-mutated tumors. (ADO 2024) - "In monotherapy, the pan-PI3K inhibitor BKM120 (activity against p110 alpha, beta, gamma, and delta isoforms) is able to induce growth inhibition and apoptosis in most of the melanoma models tested to date, whereas BYL719, an alpha-specific inhibitor, has limited antitumor activity as monotherapy...Initial in vivo test results (in ovo) on chick chorioallantoic membrane (CAM) showed reduced tumor burden and micrometastases by using the p110alpha-specific BYL719 in combination with trametinib...These data show that the combination of PI3K inhibitors with MEK inhibitors could be a new therapeutic option for melanoma patients. By using PI3Kα-selective inhibitors, potential side effects could be reduced compared to pan-PI3K inhibitors."

Clinical • IO biomarker • Melanoma • Oncology • Solid Tumor • BRAF • NRAS • PIK3CA

The combination of PI3Ki (phosphatidylinositol-3-kinase inhibitor) and MEKi (mitogen-activated protein kinase inhibitor) as a promising treatment option for melanoma patients with NRAS-mutated tumors. (ADO 2024) - "In monotherapy, the pan-PI3K inhibitor BKM120 (activity against p110 alpha, beta, gamma, and delta isoforms) is able to induce growth inhibition and apoptosis in most of the melanoma models tested to date, whereas BYL719, an alpha-specific inhibitor, has limited antitumor activity as monotherapy...Initial in vivo test results (in ovo) on chick chorioallantoic membrane (CAM) showed reduced tumor burden and micrometastases by using the p110alpha-specific BYL719 in combination with trametinib...These data show that the combination of PI3K inhibitors with MEK inhibitors could be a new therapeutic option for melanoma patients. By using PI3Kα-selective inhibitors, potential side effects could be reduced compared to pan-PI3K inhibitors."

Clinical • IO biomarker • Melanoma • Oncology • Solid Tumor • BRAF • NRAS • PIK3CA

The Impact of Dibutyl Phthalate on Insulin Signaling in Human Skeletal Muscle Cells. (PubMed, Discov Med) - "This study elucidates a molecular mechanism by which DBP induces IR in skeletal muscle cells, primarily through the deregulation of the PI3K-dependent insulin signaling pathway. These insights enhance comprehension of the pathophysiological changes associated with IR caused by environmental pollutants like DBP, potentially guiding future strategies for prevention and intervention."

Journal • AKT2 • PTEN • SLC2A4

MYC upstream region orchestrates resistance to PI3K inhibitors in cancer cells through FOXO3a-mediated autophagic adaptation. (PubMed, Oncogene) - "In response to BKM120, the upstream region of MYC (UR) enhances MYC expression, via FOXO3a, leading to increased autophagic flux and resistance to PI3K inhibitors (left). Pharmacological blockade of autophagy (center) or lack of translocated MYC UR along with MYC CDS in BL (right) overcome resistance and induces cells death. Image created in BioRender."

Journal • Burkitt Lymphoma • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • FOXO3 • MYC