Dataset Information

TEAD Inhibitors Sensitize KRAS^G12C Inhibitors via Dual Cell Cycle Arrest in KRAS^G12C-Mutant NSCLC.

ABSTRACT: KRAS^G12C is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRAS^G12C inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRAS^G12C mutant NSCLC; however, resistance to therapy is emerging. The transcriptional coactivators YAP1/TAZ and the family of transcription factors TEAD1-4 are the downstream effectors of the Hippo pathway and regulate essential cellular processes such as cell proliferation and cell survival. YAP1/TAZ-TEAD activity has further been implicated as a mechanism of resistance to targeted therapies. Here, we investigate the effect of combining TEAD inhibitors with KRAS^G12C inhibitors in KRAS^G12C mutant NSCLC tumor models. We show that TEAD inhibitors, while being inactive as single agents in KRAS^G12C-driven NSCLC cells, enhance KRAS^G12C inhibitor-mediated anti-tumor efficacy in vitro and in vivo. Mechanistically, the dual inhibition of KRAS^G12C and TEAD results in the downregulation of MYC and E2F signatures and in the alteration of the G2/M checkpoint, converging in an increase in G1 and a decrease in G2/M cell cycle phases. Our data suggest that the co-inhibition of KRAS^G12C and TEAD leads to a specific dual cell cycle arrest in KRAS^G12C NSCLC cells.

SUBMITTER: Tammaccaro SL

PROVIDER: S-EPMC10142471 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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TEAD Inhibitors Sensitize KRASG12C Inhibitors via Dual Cell Cycle Arrest in KRASG12C-Mutant NSCLC.

Tammaccaro Salvina Laura SL Prigent Philippe P Le Bail Jean-Christophe JC Dos-Santos Odette O Dassencourt Laurent L Eskandar Myriam M Buzy Armelle A Venier Olivier O Guillemot Jean-Claude JC Veeranagouda Yaligara Y Didier Michel M Spanakis Emmanuel E Kanno Tokuwa T Cesaroni Matteo M Mathieu Stephane S Canard Luc L Casse Alhassan A Windenberger Fanny F Calvet Loreley L Noblet Laurence L Sidhu Sukhvinder S Debussche Laurent L Moll Jurgen J Valtingojer Iris I

Pharmaceuticals (Basel, Switzerland) 20230406 4

KRASG12C is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRASG12C inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRASG12C mutant NSCLC; however, resistance to therapy is emerging. The transcriptional coactivators YAP1/TAZ and the family of transcription factors TEAD1-4 are the downstream effectors of the Hippo pathwa ...[more]

PMID: 37111311

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Project description:KRAS has long been referred to as an 'undruggable' target due to its high affinity for its cognate ligands (GDP and GTP) and its lack of readily exploited allosteric binding pockets. Recent progress in the development of covalent inhibitors of KRASG12C has revealed that occupancy of an allosteric binding site located between the α3-helix and switch-II loop of KRASG12C-sometimes referred to as the 'switch-II pocket'-holds great potential in the design of direct inhibitors of KRASG12C. In studying diverse switch-II pocket binders during the development of sotorasib (AMG 510), the first FDA-approved inhibitor of KRASG12C, we found the dramatic conformational flexibility of the switch-II pocket posing significant challenges toward the structure-based design of inhibitors. Here, we present our computational approaches for dealing with receptor flexibility in the prediction of ligand binding pose and binding affinity. For binding pose prediction, we modified the covalent docking program CovDock to allow for protein conformational mobility. This new docking approach, termed as FlexCovDock, improves success rates from 55 to 89% for binding pose prediction on a dataset of 10 cross-docking cases and has been prospectively validated across diverse ligand chemotypes. For binding affinity prediction, we found standard free energy perturbation (FEP) methods could not adequately handle the significant conformational change of the switch-II loop. We developed a new computational strategy to accelerate conformational transitions through the use of targeted protein mutations. Using this methodology, the mean unsigned error (MUE) of binding affinity prediction were reduced from 1.44 to 0.89 kcal/mol on a set of 14 compounds. These approaches were of significant use in facilitating the structure-based design of KRASG12C inhibitors and are anticipated to be of further use in the design of covalent (and noncovalent) inhibitors of other conformationally labile protein targets.

Dataset Information

TEAD Inhibitors Sensitize KRAS^G12C Inhibitors via Dual Cell Cycle Arrest in KRAS^G12C-Mutant NSCLC.

Publications

TEAD Inhibitors Sensitize KRAS<sup>G12C</sup> Inhibitors via Dual Cell Cycle Arrest in KRAS<sup>G12C</sup>-Mutant NSCLC.

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