Abstract 1787P
Background
RAS mutations are the most common oncogenic drivers in adenocarcinoma. KRAS is mutated in ∼30% of non-small cell lung cancer (NSCLC), majority of pancreatic adenocarcinomas and ∼40% of colorectal cancers (CRC). NF1 encodes the RAS GAP neurofibromin, functioning as an inhibitor of the MAPK pathway by facilitating the hydrolysis of RAS to its GDP-bound state. KRAS G13D is a recognised cycling mutant with NF1 GAP sensitivity, thus upstream co-mutation with NF1 is of importance to evaluate.
Methods
471 patients with advanced RAS and/or NF1 mutant NSCLC were retrospectively identified from four tertiary cancer centres using targeted NGS between 2008 –2021. Molecular, clinical and pathological outcome data were collected. Online resources cBioPortal and Project Achilles were used to validate the functional role of findings.
Results
KRAS mutations were identified in 413 patients (Table). 64 displayed a mutation (mt) in NF1, of which 25 (40%) had a concomitant KRAS mt. Of these double mutants, 12/25 (48%) had a KRAS G12C mt vs. 6/25 (24%) G13D; G13D was significantly more prevalent in double mutants than in NF1 wild type cancers (NF1 WT: 4/281, 1.4%; NF1 mutant: 6/25, 24%; p<0.0001). Although NF1 mutations are expected to be ‘passengers’, those with a G13D/NF1 co-mutation had a truncating NF1 mt and predicted oncogenic loss of function in 4/5 assessable cases. Functional analysis of NF1 knockdown in KRAS-mutant cell lines demonstrated increased knockdown sensitivity of G13D lung cancer cell lines vs. those harbouring G12C (p=0.04). Wider exploration in cBioPortal demonstrated that G13/NF1 co-mutations occurred in 11 NSCLC patients, of which 82% harboured a G13D mt, and 8 CRC patients: 100% G13D mutant. Table: 1787P
| KRAS G12C | KRAS G12D | KRAS G12V | KRAS G13X | Other KRAS | |
| Number patients | 174/413 (42%) | 69/413 (17%) | 70/413 (17%) | 24/413 (6%) | 76/413 (18%) |
| NF1 | 12/121 (10%) | 2/52 (4%) | 1/56 (2%) | 7/21 (33%) | 3/58 (5%) |
Conclusions
KRAS G13D preferentially mutates with NF1 in CRC and NSCLC, with functional importance conferred by NF1 loss. Testing upstream inhibition with EGFR/SHP2 inhibitors in KRAS G13D preclinical models will delineate their vulnerability in the context of NF1 loss.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.