Evolution of resistance to KRAS^G12Cinhibitor in a non-small cell lung cancer responder

Abstract

Despite initial therapeutic successes, most patients with non-small cell lung cancer (NSCLC) who carry the KRASG12Cmutation ultimately exhibit resistance to targeted treatments. To improve our comprehension of how acquired resistance develops, we present an unprecedented longitudinal case study profiling the transcriptome of peripheral blood mononuclear cells (PBMCs) over 5 months from an NSCLC patient with the KRASG12Cmutation and initial response to sotorasib followed by resistance and death. Single-cell RNA sequencing analysis uncovered notable fluctuations in immune cell populations throughout treatment with sotorasib. Specifically, we observed a decline in circulating CD8+CD161hiT cells correlating with periods of therapeutic response, followed by a resurgence during phases of nonresponse. This study established a high-resolution atlas detailing the evolutionary trajectory of resistance to sotorasib and characterizes a CD8+CD161hiT cells population in KRASG12Cmutation patient.