uprosertib (LAE003) / Novartis, Laekna Therap - LARVOL DELTA

Phase II study of trametinib alone and in combination with uprosertib in patients with metastatic triple negative breast cancer previously treated with chemotherapy: OSU 13317 (AACR 2024) - "Trametinib alone and in combination with uprosertib demonstrates anti-tumor activity in a subset of TNBC patients with kinome evidence of target engagment. ctDNA clearance at C2D1 may be useful as an early biomarker to identify patients most likely to respond. Understanding biomarkers of response and resistance may guide future opportunities for MEK/AKT inhibition in TNBC."

Clinical • Combination therapy • Metastases • P2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MAP2K2

Phase II study of MEK inhibitor trametinib alone and in combination with AKT inhibitor GSK2141795/uprosertib in patients with metastatic triple negative breast cancer. (PubMed, Breast Cancer Res Treat) - "In patients with mTNBC, Trametinib monotherapy demonstrated limited efficacy and addition of Uprosertib was associated with numerically greater objective responses but no difference in PFS. Translational analyses suggest ctDNA clearance as a potential early biomarker of response."

Clinical • Combination therapy • Journal • Metastases • P2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Trametinib With or Without GSK2141795 in Treating Patients With Metastatic Uveal Melanoma (clinicaltrials.gov) - P2 | N=42 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jul 2026 ➔ Jul 2027

Trial completion date • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

EPIGENETIC REGULATION OF CD52 INFLUENCES THE EXPRESSION OF AKT AND MODULATES THE CELLULAR RESPONSE TO VENETOCLAX AND UPROSERTIB IN ACUTE MYELOID LEUKEMIA (EHA 2026) - "C. Protein levels of CD52 in AML cell lines."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • AKT1 • ANXA5 • BCL2 • CD52

Gene knockout or selective inhibition of AKT-3, but not AKT-1 or AKT-2 isoform, enhances apoptosis in CD133+ melanoma cancer stem cells treated with the MEK inhibitor trametinib (AACR 2026) - "Combinational inhibition of the MAPK and PI3K/AKT pathways with trametinib and the pan-AKT inhibitor capivasertib synergistically induces melanoma cell apoptosis in vitro and inhibits tumor growth in vivo...We next investigated apoptosis induction by selective inhibitors of each of the AKT isoforms; afuresertib for AKT-1, CCT128930 for AKT-2, or uprosertib for AKT-3, as a monotherapy or in combination with trametinib...Future studies will focus on optimizing the effect of selective inhibitors of AKT-3 in dose response experiments, and test its effects in in vivo mouse xenograft studies. Simultaneously targeting the AKT and MAPK survival pathways with trametinib and uprosertib underscores the importance of combination therapies to eliminate recalcitrant melanoma stem cells."

Cancer stem • Brain Cancer • Glioblastoma • Melanoma • Oncology • Solid Tumor • AKT1 • AKT2 • ANXA5 • CD133 • NRAS

Acute and Early Circulating Tumor DNA Dynamics in Metastatic Triple-Negative Breast Cancer Targeted Therapy Phase Ib/II Clinical Trials (SABCS 2025) - P1b, P2 | "Furthermore, there is littleknown regarding TF dynamics in the hours immediately after initiation of systemic therapy –including whether there is a 'surge' in ctDNA. Banked plasma samples were identified from four completed phase Ib/II clinical trialsenrolling patients with mTNBC: heat shock protein 90 (HSP90) inhibitor onalespib with paclitaxel(NCT02474173), MEK inhibitor trametinib alone and in combination with AKT inhibitorGSK2141795/uprosertib (NCT01964924), multi-kinase inhibitor cabozantinib monotherapy(NCT02260531), and JAK1/2 inhibitor ruxolitinib monotherapy(NCT01562873)... There was no significant 'surge' in ctDNA TF within minutes to 24-hours of infusionof a targeted therapy, cytotoxic chemotherapy, or both in combination. Stability or decline ofctDNA TF 14-28 days after initiation of targeted therapy trial was associated with objectiveresponse and prolonged PFS. This supports further research on ctDNA dynamics immediatelyafter..."

Circulating tumor DNA • Clinical • Metastases • P1/2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDC37 • HSP90AA1

Trametinib With or Without GSK2141795 in Treating Patients With Metastatic Uveal Melanoma (clinicaltrials.gov) - P2 | N=42 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Completed ➔ Active, not recruiting | Trial completion date: Sep 2017 ➔ Jul 2026

Enrollment closed • Trial completion date • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

AKT inhibitors in gynecologic oncology: past, present and future. (PubMed, Front Oncol) - "Currently, multiple classes of AKT inhibitors-PH domain competitors (perifosine), allosteric inhibitors (MK-2206), and ATP-competitive agents (AZD5363, GSK2110183, GSK2141795, and GDC-0068) are under development, with several agents in phase II/III trials. This study systematically reviews recent AKTi research in gynecological cancers, aiming to provide a theoretical foundation for identifying potential biomarkers, overcoming drug resistance, and developing prognostic models. These insights may further facilitate the clinical translation of key therapeutic agents."

Journal • Review • Gynecologic Cancers • Oncology

Integrated transcriptomic and functional modeling reveals AKT and mTOR synergy in colorectal cancer. (PubMed, Sci Rep) - "Among the tested combinations, everolimus (mTOR inhibitor) and uprosertib (AKT inhibitor) demonstrated promising synergy at clinically relevant concentrations, with favorable therapeutic windows confirmed across tested patient-derived cultures. Our findings underscore the potential of patient-derived materials combined with machine learning-enhanced drug discovery to advance personalized therapies. Specifically, mTOR-AKT inhibition emerges as a promising strategy for CRC treatment, paving the way for more effective and targeted therapeutic approaches."

Journal • Colorectal Cancer • Oncology • Solid Tumor

CD52 PROMOTER METHYLATION PREDICTS RESPONSE TO AKT-TARGETING DRUGS IN ACUTE MYELOID LEUKEMIA (EHA 2025) - "Sensitivity to Akt inhibitors (Uprosertib/Afuresertib) was tested in ten wild-type (WT) cell lines and SET-2 shRNA model via MTT. CD52, an indicator of poor prognosis in AML, is associated with Akt expression in cell lines and patients. This seems to contribute to an aggressive phenotype characterized by enhanced cell proliferation and viability, resulting in a reduced survival rate in AML patients. This finding underlines the potential of targeting Akt in AML depending on the CD52 methylation profile, based on the favorable results obtained in vitro."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CD52

SWOG-S1221: Uprosertib, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer (clinicaltrials.gov) - P1/2 | N=27 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed

Trial completion • Cutaneous Melanoma • Hematological Malignancies • Melanoma • Oncology • Solid Tumor

SWOG-S1221: Uprosertib, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer (clinicaltrials.gov) - P1/2 | N=27 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2024 ➔ Oct 2025

Combination therapy • Trial completion date • Cutaneous Melanoma • Hematological Malignancies • Melanoma • Oncology • Solid Tumor

A phase 1 study of triple-targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF-mutated cancers. (PubMed, Cancer) - P1/2 | "Concomitant inhibition of both the MAPK and PI3K-AKT pathways for the treatment of BRAF-mutated cancers was well tolerated, leading to objective responses, but higher level drug-drug interactions affected exposure to dabrafenib and its metabolites."

Journal • P1 data • Endocrine Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma

SWOG-S1221: Uprosertib, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer (clinicaltrials.gov) - P1/2 | N=27 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2023 ➔ Oct 2024

Combination therapy • Trial completion date • Cutaneous Melanoma • Hematological Malignancies • Melanoma • Oncology • Solid Tumor

Comprehensive analysis of angiogenesis pattern and related immune landscape for individual treatment in osteosarcoma. (PubMed, NPJ Precis Oncol) - "OS patients with high ANGscore might be resistant to uprosertib, and be sensitive to VE821, AZD6738 and BMS.345541. In conclusion, we established a novel ANGscore system by comprehensively analysing the expression pattern of angiogenesis genes, which can accurately differentiate the prognosis and immune characteristics of OS populations. Additionally, the ANGscore can be used for patient stratification during immunotherapy, and guide individualized treatment strategies."

IO biomarker • Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • IFNG

Suxiao Jiuxin Pill attenuates acute myocardial ischemia via regulation of coronary artery tone. (PubMed, Front Pharmacol) - "Vasodilation caused by senkyunolide A and scopoletin was inhibited by uprosertib (Akt inhibitor) and eNOS/sGC/PKG axis inhibitors...The K channel inhibitor 4-AP, K inhibitor TEA, and K inhibitor BaCl significantly inhibited the vasorelaxant effect of borneol in the coronary artery. In conclusion, the results show that Suxiao Jiuxin Pill protects the heart against acute myocardial infarction."

Journal • Cardiovascular • Heart Failure • Myocardial Infarction • Myocardial Ischemia • NOS3 • PACERR • PTGS2

Phase I/II Study of the Safety and Efficacy of the AKT Inhibitor GSK2141795 in Combination with the BRAF Inhibitor Dabrafenib and Trametinib in Patients with BRAF Mutant Cancer (SWOG-Fall 2022) - No abstract available

Clinical • Combination therapy • P1/2 data • Oncology

[VIRTUAL] Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated head and neck squamous cell carcinoma (AACR-NCI-EORTC 2020) - P2 | "In this study we explored the activity of tipifarnib in cellular models and six HRAS-mutant and twelve HRAS WT HNSCC patient-derived xenograft models alone and in combination with clinical stage inhibitors of PI3K-a (alpelisib), AKT (uprosertib) and mTORC1/2 (sapanisertib). Regressions with the FTI-PI3K-a inhibitor doublet were observed both in tumors that were WT or with PIK3CAmutations or amplification and in HRAS mutants that carried or lacked PIK3CA mutations, suggesting concomitant blockade of both targets may have broad and potent anti-tumor activity in HNSCC. Additional biomarkers associated with sensitivity or resistance and alterations in gene expression (by RNAseq) and oncogenic signaling following treatment either as a monotherapy or in combinations will be reported."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP8 • HRAS • PIK3CA • TP53

[VIRTUAL] Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated head and neck squamous cell carcinoma (AACR-NCI-EORTC 2020) - P2 | "In this study we explored the activity of tipifarnib in cellular models and six HRAS-mutant and twelve HRAS WT HNSCC patient-derived xenograft models alone and in combination with clinical stage inhibitors of PI3K-a (alpelisib), AKT (uprosertib) and mTORC1/2 (sapanisertib). Regressions with the FTI-PI3K-a inhibitor doublet were observed both in tumors that were WT or with PIK3CAmutations or amplification and in HRAS mutants that carried or lacked PIK3CA mutations, suggesting concomitant blockade of both targets may have broad and potent anti-tumor activity in HNSCC. Additional biomarkers associated with sensitivity or resistance and alterations in gene expression (by RNAseq) and oncogenic signaling following treatment either as a monotherapy or in combinations will be reported."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP8 • HRAS • PIK3CA • TP53

SWOG-S1221: Uprosertib, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer (clinicaltrials.gov) - P1/2 | N=27 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2022 ➔ Oct 2023

Combination therapy • Trial completion date • Cutaneous Melanoma • Hematological Malignancies • Melanoma • Oncology • Solid Tumor

FOXO1 Alleviates Liver Ischemia-reperfusion Injury by Regulating the Th17/Treg Ratio through the AKT/Stat3/FOXO1 Pathway. (PubMed, J Clin Transl Hepatol) - "The AKT/Stat3/FOXO1 pathway was verified by targeting AKT with GSK2141795...Liver IRI induced Th17/Treg imbalance. Upregulation of FOXO1 reversed the imbalance and alleviated liver inflammation."

Journal • Cardiovascular • Hepatology • Immunology • Inflammation • Liver Failure • Reperfusion Injury • FOXO1

SWOG S1221: A phase 1 dose escalation study co-targeting MAPK-dependent and MAPK-independent BRAF inhibitor resistance in BRAF mutant advanced solid tumors with dabrafenib, trametinib, and GSK2141795 (ClinicalTrials.gov NCT01902173). (ASCO 2017) - P1/2; "Inhibition of both MAPK and PI3K/AKT pathways was well tolerated, leading to durable objective responses in pts with metastatic melanoma, thyroid cancer, and lung cancer. Further study of dual pathway inhibition is warranted."

Clinical • P1 data • Biosimilar • Lung Cancer • Melanoma • Thyroid Gland Carcinoma

A single arm, single stage phase II trial of trametinib (GSK1120212) and GSK2141795 in persistent or recurrent cervical cancer (AACR 2017) - "Abstract embargoed at this time."

Clinical • P2 data • Biosimilar • Cervical Cancer • Oncology

Targeting Akt/PKB in Pediatric Tumors: A Review From Preclinical to Clinical Trials. (PubMed, Pharmacol Res) - "This review summarizes recent available evidence of Akt inhibitors in pediatric cancers, from both preclinical and clinical studies. In short, we demonstrate the impact that Akt inhibition provides in tumorigenesis, and we suggest targeting the PI3K/Akt/mTOR signaling pathway, alone or in combination with other inhibitors, is a feasible tool to achieve better outcomes in pediatric tumors."

Journal • Preclinical • Review • Oncology • Pediatrics

An effective AKT inhibitor-PARP inhibitor combination therapy for recurrent ovarian cancer. (PubMed, Cancer Chemother Pharmacol) - "Collectively, our results suggest that the combination of AKT inhibitor and PARP inhibitor could be a viable approach for clinical testing in recurrent ovarian cancer patients."

Combination therapy • Journal • Oncology • Ovarian Cancer • Solid Tumor