GSE137912
Single cell RNA sequencing of cells treated with a KRAS G12C specific inhibitor
KRAS GTPases are activated in one-third of cancers and KRASG12C is the most common activating alteration in lung adenocarcinoma. KRASG12C inhibitors are in Phase-I clinical trials and early data show partial responses in ~50% of lung cancer patients. How cancer cells bypass inhibition, to prevent maximal response to therapy, is not understood. By studying the effect of treatment at single-cell resolution here we found that shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, while others bypass this effect to resume proliferation. We then identified adaptive changes that lead to this rapid divergent response and how these differ between cancer cell subpopulaitons. This study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic. Overall design: KRAS G12C-mutant tumor cell models (H358, H2122 and SW1573) were treated with the KRAS G12C (ARS1620, 10µM) inhibitor for 0, 4, 24 and 72h, followed by rapid collection of attached cells in cryopreservation medium. The cells were stored in -80oC until the completion of the experiment. scRNAseq was carried out using the Chromium 10X platform (3-prime v1 kit), as described in the manufacturer's protocol.