Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(7), P. 1556 - 1571

Published: April 17, 2023

Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations KEAP1, SMARCA4, CDKN2A as major independent determinants inferior clinical outcomes KRASG12Ci monotherapy. Collectively, comutations these three tumor suppressor genes segregated into distinct prognostic subgroups captured ∼50% those early disease progression (progression-free survival ≤3 months) KRASG12Ci. Pathway-level integration less prevalent functionally related nominated PI3K/AKT/MTOR pathway additional baseline RAS gene alterations, including amplifications, candidate drivers KRASG12Ci, revealed possible association between defective DNA damage response/repair improved efficacy. Our findings propose framework for patient stratification outcome prediction that can inform rational selection appropriate tailoring emerging combination therapies. this work, identify co-occurring genomic alterations poor monotherapy NSCLC, treatment personalization based on the comutational status individual tumors. See commentary by Heng et al., p. 1513. This article is highlighted Issue feature, 1501.

Language: Английский

---

Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy

Nature, Journal Year: 2024, Volume and Issue: 629(8013), P. 919 - 926

Published: April 8, 2024

Abstract RAS oncogenes (collectively NRAS , HRAS and especially KRAS ) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 61 1 . Small molecule inhibitors of KRAS(G12C) oncoprotein have demonstrated clinical efficacy patients multiple cancer types led to regulatory approvals for treatment non-small cell lung 2,3 Nevertheless, G12C account only around 15% -mutated cancers 4,5 there no approved majority tumours containing other mutations. Here we describe RMC-7977, a reversible, tri-complex inhibitor broad-spectrum activity active state both mutant wild-type KRAS, variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 potent against RAS-addicted carrying various genotypes, particularly models codon 12 ( G12X ). Treatment tumour regression was well tolerated diverse preclinical models. Additionally, inhibited growth that resistant owing restoration pathway signalling. Thus, can target oncogenic isoforms potential treat wide range high unmet need. A related inhibitor, RMC-6236, is currently under evaluation -mutant solid (ClinicalTrials.gov identifier: NCT05379985).

Language: Английский

---

An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance

Nature Cancer, Journal Year: 2023, Volume and Issue: 4(6), P. 812 - 828

Published: June 5, 2023

Abstract The Hippo pathway is a key growth control that conserved across species. downstream effectors of the pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation survival. Based on premise sustained interactions between YAP/TAZ TEADs enhanced associate domain) central their transcriptional activities, we discovered potent small-molecule inhibitor (SMI), GNE-7883, allosterically blocks all human TEAD paralogs through binding lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at motifs, suppresses cell variety line models achieves strong antitumor efficacy vivo. Furthermore, uncovered overcomes both intrinsic acquired resistance KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors diverse preclinical inhibition activation. Taken together, this work demonstrates activities SMIs YAP/TAZ-dependent highlights potential broad applications precision oncology therapy resistance.

Language: Английский

---

Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C

Cancer Discovery, Journal Year: 2022, Volume and Issue: 12(6), P. 1500 - 1517

Published: April 4, 2022

Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor GDP-bound that forms novel interactions with the switch II pocket. potently inhibits KRASG12C-driven cellular signaling demonstrates selective antiproliferative in cell lines, including those G12C/H95 double mutations. In vivo, induces AUC exposure-driven efficacy cell-derived (CDX) patient-derived (PDX) tumor xenografts. PDX models, single-agent enhanced by combination SHP2, MEK, or CDK4/6. Notably, benefit plus SHP2 TNO155 maintained at reduced doses either agent CDX consistent mechanistic synergy. clinical development as monotherapy TNO155, both showing patients tumors. binding mode potent lines vivo models. preclinical models malignancies, shows TNO155. This article highlighted Issue feature, p. 1397.

Language: Английский

---

Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non–Small Cell Lung Cancer

Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 28(15), P. 3318 - 3328

Published: April 11, 2022

Abstract Purpose: Patients with KRAS-mutant non–small cell lung cancer (NSCLC) brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), potent oral small-molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. has been optimized for favorable pharmacokinetic properties, including long half-life (∼24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, central nervous system penetration; however, BM-specific antitumor activity of inhibitors remains to be fully characterized. Experimental Design: A retrospective database query identified patients NSCLC understand their propensity develop BM. Preclinical studies assessed physiochemical properties adagrasib. Mice bearing intracranial KRASG12C-mutant xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated clinically relevant adagrasib doses, levels plasma, cerebrospinal fluid (CSF), determined along activity. Preliminary clinical data collected from 2 untreated BM who had received 600 mg twice daily the phase Ib cohort KRYSTAL-1 trial; CSF was collected, concentrations measured, evaluated. Results: demonstrated high (≥40%). penetrated into tumor regression extended survival multiple preclinical models. In BM, measured above target cellular IC50. Both corresponding regression, supporting potential brain. Conclusions: These support further development See related commentary by Kommalapati Mansfield, p. 3179

Language: Английский

---