Multi-region sequencing efforts of primary and metastatic tumors highlighted convergent evolution on critical cancer genes through site-specific private alterations, despite genetic divergence among temporally and spatially separated lesions. About 32% and 13% of LUAD harbor KRAS and KRAS G12C mutations, respectively. Among others, acquired oncogenic alterations in RAS/RAF and NF1 were associated with resistance to KRAS G12C inihibitors. We hypothesized that a subset of KRAS-mutated LUAD not previously exposed to KRAS-directed therapies could harbor genetic alterations associated with resistance to KRAS inhibitors.
We analyzed publicly available multi-sample sequencing data from the TRACERx and GENIE BPC NSCLC v2.0; we included patients with KRAS-mutated LUAD on at least one tumor sample and excluded patients harboring other known actionable mutations or gene fusions. We only selected OncoKB-annotated and FATHMM/PolyPhen-2 predicted pathogenic RAS, RAF and NF1 mutations. We used the TCGA LUAD dataset as a reference for single-sample sequencing.
TRACERx: among 24 KRAS-mutated patients, 7 (29%) patients had a concomitant oncogenic alteration in RAS, RAF or NF1; among 7 KRAS G12C-mutated patients, 3 patients had concomitant oncogenic alterations (KRAS G12V and NF1 G26V; RAF1S339G; BRAF D594N). GENIE BCP NSCLC: among 31 KRAS-mutated patients, 13 (42%) patients had a concomitant oncogenic alteration in RAS, RAF or NF1; among 16 KRAS G12C-mutated patients, 7 (44%) patients had concomitant oncogenic alterations (NF1 R2364W; KRAS G12V, KRAS V8L and NF1 D186Y; BRAF A561S and NF1 X465_splice; KRAS G12V; NF1_X803_splice; KRAS G12V and NF1 A138D; ARAF S257I). TCGA LUAD: among 168 KRAS-mutated patients, 13 (8%) patients had a concomitant oncogenic alteration in RAS, RAF or NF1; among 70 KRAS G12C-mutated patients, 7 (10%) patients had concomitant oncogenic alterations (BRAF A762E; NF1 G520R; NF1 D2482N; KRAS G12V, two patients; KRAS G12D; NF1 L2413_Fs).
RAS, RAF and NF1 oncogenic mutations are found in up to 42% of KRAS-mutated LUAD through multi-sample sequencing, while their frequency is markedly lower in tumor sequenced in a single region. This finding has profound implications in patients' selection for KRAS-directed therapies.
The authors.
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All authors have declared no conflicts of interest.