sapanisertib (CB-228) / Calithera - LARVOL DELTA

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

Phase I study of mTORC1/2 inhibitor sapanisertib in combination with metformin in patients with mTOR/AKT/PI3K pathway alterations and advanced solid malignancies. (PubMed, Cancer Res Commun) - "The safety profile of mTORC1/2 inhibitor sapanisertib in combination with metformin was generally tolerable, with anti-tumor activity observed in patients with advanced malignancies harboring PTEN/ AKT/mTOR pathway alterations."

Combination therapy • Journal • Metastases • P1 data • Breast Cancer • Diabetes • Dyslipidemia • Fatigue • Hypertriglyceridemia • Leiomyosarcoma • Metabolic Disorders • Oncology • Sarcoma • Solid Tumor • PIK3CA • STK11 • TSC1

Results of a phase 1b study of osimertinib plus sapanisertib or alisertib for osimertinib-resistant, EGFR-mutant non–small cell lung cancer (NSCLC). (ASCO 2022) - P1 | "Osimertinib with alisertib or sapanisertib is well tolerated in osimertinib-resistant, EGFR mutant NSCLC. The sapanisertib combination, but not the alisertib combination, demonstrates antitumor activity suggesting that mTOR inhibition warrants further exploration in this population. Biomarker analysis is ongoing to identify the molecular determinants of response and resistance to sapasertib."

P1 data • Anemia • Dental Disorders • Diabetes • Hematological Disorders • Leukopenia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Stomatitis • AURKA • EGFR

Phase I study of sapanisertib (CB-228/TAK-228/MLN0128) in combination with ziv-aflibercept in patients with advanced solid tumors. (PubMed, Cancer Med) - "The combination of sapanisertib and ziv-aflibercept was generally tolerable and demonstrated anti-tumor activity in heavily pre-treated patients with advanced malignancies."

Combination therapy • Journal • Metastases • P1 data • Anorexia • Cardiovascular • Dyslipidemia • Fatigue • Hypertension • Hypertriglyceridemia • Mucositis • Oncology • Sarcoma • Solid Tumor • HIF1A

Characterising the efficacy of multi-node PI3K/AKT/mTOR pathway inhibition with serabelisib and sapanisertib (PIKTOR) in combination with SERDs and CDK inhibitors in models of HR+/HER2- breast cancer (ESMO 2026) - No abstract available

Clinical • Combination therapy • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

A recurrently perturbed 12-gene program marks drug-tolerant persister states across cancer types. (PubMed, Front Bioinform) - "INK128-induced DTP models in MCF-7 and HCT116 cells demonstrated cell-cycle arrest, morphological changes, and RT-qPCR confirmation of PanDTP-12 upregulation (12/12 significant in HCT116; 6/12 in MCF-7)...These findings identify PanDTP-12 as a recurrently perturbed twelve-gene program marking the DTP state across cancer types. The signature offers focused pharmacological hypotheses through druggable members (CLK1, XBP1, and KLF5) and establishes a framework for translational assessment of DTP-directed therapeutics, though larger validation cohorts and functional studies will be needed to confirm clinical utility."

Journal • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KLF5 • XBP1

Targeting the 4EBP1/HSP90β/Nrf2 Axis Sensitizes β-catenin-mutant Hepatocellular Carcinoma to mTOR Inhibitors via Ferroptosis Induction. (PubMed, J Clin Transl Hepatol) - "4EBP1A4 enhances Nrf2 ubiquitination and degradation via the HSP90β/Keap1 axis, relieving mTOR-mediated ferroptosis suppression and synergistically improving rapamycin efficacy. Additionally, rapamycin, MLN0128, and PD901 suppress HCC progression by inducing ferroptosis, with their combination showing superior potency."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CDC37 • CTNNB1 • EIF4EBP1 • KEAP1 • MET • RPS6

A dataset supporting Combinatorial Proteome Integral Solubility/Stability Alteration Analysis (CoPISA). (PubMed, Sci Data) - "The dataset includes two AML drug pairs (LY3009120-sapanisertib and ruxolitinib-ulixertinib) applied to four AML cell lines (MOLM-13, MOLM-16, SKM-1, and NOMO-1) under control, single-agent, and combination conditions in both lysate and intact-cell formats. All data are publicly available through the PRIDE repository (PXD066812) together with analysis code, enabling independent reanalysis and method development. This dataset provides a benchmark resource for studying proteome responses to drug combinations, comparing lysate and intact-cell perturbation profiles, developing computational approaches for combinatorial target inference, and supporting training in computational proteomics."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Genome-wide copy number analysis identifies AKT as a novel therapeutic target in pleural mesothelioma. (PubMed, Lung Cancer) - "Our study demonstrates recurrent activation of AKT kinases by copy number gains and upregulated expression in PM. Pharmacological AKT and mTOR inhibition is a promising therapeutic alternative for mesothelioma."

Journal • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • AKT2

Testing the Combination of MLN0128 (TAK-228) and AZD9291 in Advanced EGFR (Epidermal Growth Factor Receptor) Mutation Positive Non-small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=36 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Feb 2027 | Trial primary completion date: Jun 2026 ➔ Feb 2027

Trial completion date • Trial primary completion date • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Scope and Automation of Internal Heterocyclic 11C-labeling with [11C]CNBr (SNMMI 2026) - "This method has also been applied to a successful automated radiosynthesis of the mTORC-1/2 inhibitor [11C]Sapanisertib, suggesting its feasibility for clinical PET radioligand production... We present efficient methods for the radiosynthesis of internally labeled 11C-heteroarenes. This method has broad applicability for disparate heterocyclic examples and finds utility in accessing (radio)pharmaceutical scaffolds without structural modification. The application of microwave heating also shows the feasibility of microwave-accelerated 11C-radiolabeling in a broader context."

Scope and Automation of Internal Heterocyclic 11C-labeling with [11C]CNBr (SNMMI 2026) - "This method has also been applied to a successful automated radiosynthesis of the mTORC-1/2 inhibitor [11C]Sapanisertib, suggesting its feasibility for clinical PET radioligand production... We present efficient methods for the radiosynthesis of internally labeled 11C-heteroarenes. This method has broad applicability for disparate heterocyclic examples and finds utility in accessing (radio)pharmaceutical scaffolds without structural modification. The application of microwave heating also shows the feasibility of microwave-accelerated 11C-radiolabeling in a broader context."

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

mTOR inhibition enhances the antitumor efficacy of pan-RAF-MEK blockade by inhibiting the ATF4-MTHFD2 pathway. (PubMed, Cell Death Dis) - "Human and murine models resistant to combined belvarafenib and cobimetinib exhibited elevated levels of ATF4 and MTHFD2 and were sensitive to sapanisertib. This study provides promising treatment opportunities for patients with non-BRAF-mutant melanomas, or those who relapse following belvarafenib and cobimetinib combination therapy."

Journal • Melanoma • Oncology • Solid Tumor • ATF4 • MTHFD2 • NF1 • NRAS

Sapanisertib and Serabelisib (PIKTOR) in Various Combinations in Patients With HR+/HER2- Advanced/Metastatic Breast Cancer (clinicaltrials.gov) - P1/2 | N=32 | Recruiting | Sponsor: Faeth Therapeutics

New P1/2 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Spatially resolved ex vivo drug response profiling in SMARCB1-deficient sinonasal carcinoma. (PubMed, EMBO Mol Med) - "Ex vivo drug testing revealed a striking response: the mTOR inhibitor Sapanisertib induced extensive tumor necrosis and was associated with near-complete depletion of ALDH1A1+ and NTN4+ states, accompanied by strong stress/apoptosis signatures and reduced endothelial cells. In an additional retrospective cohort of 12 SDSC, ALDH1A1 was present in all cases with heterogeneous spatial patterns and higher levels in recurrences. Mesothelin was expressed in the index case and a subset of tumors, supporting mesothelin-directed therapeutic strategies."

Journal • Preclinical • Oncology • ALDH1A1 • MSLN • SMARCB1 • TP63

Adaptive resistance mechanisms to mTOR inhibitor in lung squamous cell carcinoma (AACR 2026) - "Moreover, prolonged treatment of LUSC PDXs with TAK228 and the glutaminase inhibitor CB-839 led to upregulation of vascularization, which coincided with a rebound in tumor growth despite continued therapeutic administration. These findings highlight adaptive resistance mechanisms to small molecule inhibitors that target key metabolic pathways, lending insight into potential future clinical strategies for the treatment of LUSC."

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

The future of urothelial carcinoma: a 2024-2025 update of early-phase trials of novel therapeutic agents. (PubMed, Curr Opin Urol) - "The findings indicate a shift towards more effective and tailored treatments. Future efforts must focus on biomarker validation, strategic sequencing, and managing combination toxicities to integrate these advances into practice and improve patient outcomes."

IO biomarker • Journal • Review • Oncology • Solid Tumor • Urothelial Cancer

Improving targeted therapy in female patients with lung squamous cell carcinoma (AACR 2024) - P1, P2 | "Follow-on experiments have demonstrated that the anti-estrogen therapy (Letrozole) sensitized previously resistant female mice bearing LUSCs to TAK228, suggesting an estrogen-related link to TAK228 resistance in females. These results suggest that the estrogen may play a key role in the observed pattern of female resistance to mTOR inhibition. As such, the goal of the current proposal is to evaluate the catalytic mTOR kinase inhibitor TAK228, in combination with anti-estrogen therapy as a therapeutic strategy to treat LUSC in females."

Clinical • 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

Evaluation of combination strategies with RAS-targeted inhibitors in multi-cell type spheroids (AACR 2025) - "As single agents, the KRAS-G12C inhibitors RMC-6291 and divarasib, along with the KRAS-G12D inhibitor MRTX-1133, demonstrated selective activity against the mct tumor spheroids harboring the targeted variants. In contrast, the pan-RAS(ON) inhibitor RMC-6236 demonstrated activity against the mct tumor spheroids harboring a range of KRAS variants or wild-type KRAS...In tumor models harboring different KRAS variants, the pan-RAS(ON) inhibitor showed increased cytotoxicity with the MEK inhibitor cobimetinib, as well as PI3K-AKT-mTOR pathway inhibitors, such as inavolisib (PI3Kα), ipatasertib (AKT), and sapanisertib (mTORC1/2). When the same agents were combined with variant-specific KRAS inhibitors similar effects were observed in mct tumor spheroids carrying the corresponding RAS variant. These preclinical findings might provide guidance for the selection of combination regimens with KRAS inhibitors to improve clinical efficacy."

Oncology • Solid Tumor • KRAS • PIK3CA

PI3K-AKT-mTOR signaling pathways play important roles in chromosomal instability-induced innate immune response in cancer cells (AACR 2024) - "CENP-Ei-induced CIN potently activates innate immune response pathways in cancer cells, in which PI3K-AKT-mTOR signaling pathway appears to be involved. We are initiating AI-based drug discovery to develop novel CENP-E inhibitors."

IO biomarker • Oncology

KEAP1 loss-of-function modulates ROS and AKT-mTOR pathway leading to resistance to KRAS inhibitor (AACR 2025) - "These observations underscore the broader role of KEAP1 mutations in enhancing tumor adaptability and survival under diverse therapeutic pressures.In conclusion, our results suggest that combinatorial therapeutic approaches targeting glutaminase (e.g., CB-839) and mTOR pathways (e.g., TAK-228) hold promise for overcoming resistance in KEAP1-mutant tumors. These strategies may restore sensitivity to KRAS G12C inhibitors and improve clinical outcomes.*These authors are co-first authors; #These authors are co-corresponding authors"

Late-breaking abstract • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KEAP1 • KRAS

An alternative strategy for lung cancer treatment: Targeting mTORC2 (ELCC 2026) - "Compared with the pan-mTOR inhibitor TAK228 (MTD = 1–4 mpk), LIT0922 achieved a much higher tolerated dose (160 mpk) and greater systemic exposure. It displayed strong efficacy in multiple models—NCI-H446 (SCLC), NCI-460 (NSCLC), and EGFR-TKI-resistant H1975 and HCC827 lines—and potently inhibited induced Osimertinib-resistant H1975 cells (IC50 = 0.41 nM)...Its broad antitumor activity and anti-angiogenic effect support its potential as a novel lung cancer therapy. A Phase I trial has begun, with initial results expected in 2026."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RICTOR • TSC1

Solubility based mechanistic profiling of combinatorial drug therapy. (PubMed, Nat Commun) - "We applied CoPISA to two rationally designed AML drug pairs, LY3009120-sapanisertib (LS) and ruxolitinib-ulixertinib (RU), previously identified as the most effective and least toxic combinations among many candidates and validated in AML cell lines, patient-derived samples and zebrafish xenograft models. Network analysis demonstrated that a substantial fraction of AML-associated proteins targeted by CoPISA are unique to combinations, including DNMT3A, NPM1, and TP53. By uncovering a mechanistic layer beyond classical synergy, CoPISA provides a robust framework for the precision-guided design of combinatorial therapies in heterogeneous cancers."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • DNMT3A • NPM1 • TP53