Evolution of resistance to KRASG12Cinhibitor in a non-small cell lung cancer responder

Despite initial therapeutic successes, most patients with non-small cell lung cancer (NSCLC) who carry the KRAS G12C mutation 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 KRAS G12C mutation 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 + CD161 hi T 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 + CD161 hi T cells population in KRAS G12C mutation patient.