Uncovering adagrasib resistance

Abstract

0123456789();: Nature reviews | CliniCal OnCOlOgy The novel KRASG12Cspecific inhibi tors sotorasib and adagrasib are emerging as promising targeted therapies for patients with KRASG12Cmutant cancers, in particular nonsmallcell lung cancer (NSCLC). Now, new data provide insight on the diverse mechanisms underlying resistance to adagrasib. This study involved patients with KRASG12Cmutant cancers who had disease progression on single-agent adagrasib after stable disease, or a partial or complete response for a mini mum of 12 weeks. The majority of patients (n = 27) had NSCLC, 10 had colorectal cancer (CRC) and one had apendiceal cancer. Tumour tissue, circulating tumour DNA (ctDNA) or both obtained at the time of progression were available for 10, 32 and 4 patients, respectively. Putative mechanisms of resistance were identified in 17 of 38 patients (45%), and can be classified into three main categories. The first includes novel secondary mutations or amplifications in KRAS, identified in seven patients. Five of these mutations affected the switch II pocket of KRAS, where adagrasib and sotorasib bind. The effect of these mutations was further characterized in Ba/F3 cells expressing KRASG12C, which are sensitive to both inhibitors. In doublemutant Ba/F3 cells, each of the five switch II mutations conferred resistance to adagrasib, but two of them did not confer resistance to sotorasib, suggesting the existence of drug-specific mechanisms of resistance. The second group of mechanisms includes oncogenic alterations in genes involved in receptor tyrosine kinase–RAS–MAPK signalling other than KRAS, such as NRAS, BRAF or MAP2K. These alterations were detected in 14 patients, three of whom had oncogenic fusions. Finally, the analysis of repeat tissue biopsy samples revealed histological transformation from lung adenocarcinoma to squamouscell carcinoma in two patients. No genomic mechanisms of resistance were identified. TA R G E T E D T H E R A P I E S