Co-mutations and KRAS G12C inhibitor efficacy in advanced NSCLC
Molecular modifiers of KRAS G12C inhibitor (KRAS G12Ci) efficacy in advanced KRAS G12C -mutant NSCLC are poorly defined. In a large unbiased clinico-genomic analysis of 424 NSCLC patients, we identified and validated co-alterations in KEAP1, SMARCA4 and CDKN2A as major independent determinants of in...
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Veröffentlicht in: | Cancer discovery 2023-07, Vol.13 (7), p.1556-1571 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Molecular modifiers of KRAS G12C inhibitor (KRAS G12Ci) efficacy in advanced
KRAS
G12C
-mutant NSCLC are poorly defined. In a large unbiased clinico-genomic analysis of 424 NSCLC patients, we identified and validated co-alterations in
KEAP1, SMARCA4
and
CDKN2A
as major independent determinants of inferior clinical outcomes with KRAS G12Ci monotherapy. Collectively, co-mutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ~50% of those with early disease progression (PFS≤3 months) with KRAS G12Ci. Pathway-level integration of less prevalent co-alterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRAS G12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRAS G12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in
KRAS
G12C
-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. |
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ISSN: | 2159-8274 2159-8290 |
DOI: | 10.1158/2159-8290.CD-22-1420 |