Impact of RAS-MAPK Pathway Genetic Alterations on Radiotherapy Response in Metastatic Lung Adenocarcinoma.

Abstract

To determine whether driver gene alterations in metastatic non-small cell lung carcinoma (NSCLC) spine metastases are associated with local tumor control after radiotherapy (RT). Patients with NSCLC who underwent RT for spine metastasis and tumor genetic profiling were ascertained. Associations between driver gene mutations incidence of local failure were analyzed, followed by competing risk analysis for significant associations. The results were validated using in vitro clonal survival assays of CRISPR-engineered NSCLC cell lines. A total of 181 patients were analyzed, with a median follow-up of 15.2 months (IQR, 8.0-31.9 months). The 3-year risk of local failure was 0.15 (95% CI, 0.10 to 0.20). Patients harboring <i>NF1</i> or <i>BRAF</i> driver alterations experienced higher 3-year local failure rates (<i>NF1</i>: 0.33 [0.09-0.61] <i>v</i> 0.13 [0.09-0.19]; <i>P</i> = .002); <i>BRAF</i>: 0.31 [0.08-0.57] <i>v</i> 0.13 [0.09-0.19]; <i>P</i> = .04). <i>NF1</i> loss-of-function mutations conferred radioresistance in one of two NSCLC cell lines tested in vitro. Based on the convergence of <i>NF1</i> and <i>BRAF</i> signaling, the <i>RAS-</i>mitogen-activated protein kinase (<i>MAPK</i>) pathway was further interrogated. <i>KRAS</i> mutations overall were not associated with local failure. However, comutation of <i>KRAS</i>/<i>TP53</i> exhibited a trend toward elevated 3-year local failure, 0.31 (0.11-0.55) versus 0.13 (0.08 <i>v</i> 0.19), <i>P</i> = .05. <i>RAS-MAPK</i> pathway driver alterations accounted for 53% of all local failures (<i>P</i> < .0001) and showed an elevated 3-year risk of local failure (0.36 [0.2-0.51] <i>v</i> 0.09 [0.05-0.15]; <i>P</i> < .001), including when treated with stereotactic body RT (0.28 [0.1-0.5] <i>v</i> 0.05 [0.02-0.11]; <i>P</i> = .001). Driver alterations in the <i>RAS-MAPK</i> signaling pathway confer radioresistance in metastatic NSCLC. These genetic alterations may serve as biomarkers to personalize RT strategies or as targets to enhance radiosensitivity.