Development of acquired resistance to sotorasib in NCI-H358 cell line in vitro

NCI-H358 is a KRAS G12C-mutant non-small lung cancer cell line known to be sensitive to KRAS G12C-inhibitor sotorasib. Here, we aimed to develop sotorasib resistance in H358 and interrogate the resulting sotorasib-resistant cell line (H358-R). The H358-R cell line was created by continuous culturing of the H358 cells in sotorasib (250 nM) until cells grew readily under sotorasib pressure (approximately 2 months). We then performed RNA-seq of the resulting sotorasib-resistant cell line (H358-R) with and without sotorasib pressure, compared to the parental sensitive cell line control (H358). KRAS gene expression level was found to be increased in the sotorasib-resistant line compared with the parental cells, likely representing a mechanism of resistance. The increased KRAS expression level in the resistant cell line was maintained under sotorasib pressure. RNA-seq was performed in three sample groups: (1) parental sotorasib-sensitive H358 cell line; (2) sotorasib-resistant H358-R cell line without sotorasib pressure; (3) sotorasib-resistant H358-R cell line under sotorasib pressure (250 nM, profiled 4 days after dosing). Three biological replicates were profiled per sample group.