Generating drug resistance models in human and murine cancer cell lines and assessing cross-resistance to chemotherapeutics and KRAS inhibitors

Drug resistance and cross-resistance limit the durability of cancer therapies, yet reproducible in vitro techniques for generating resistant models remain limited. Here, we present a protocol for generating human and murine cancer cell lines with drug resistance to chemotherapeutics and KRAS inhibitors. We describe steps for generating, expanding, and maintaining resistant cells. We then detail procedures for validating drug resistance and cross-resistance, followed by a quantitative killing assay. This approach facilitates the evaluation of resistance and cross-resistance liabilities of compounds. For complete details on the use and execution of this protocol, please refer to Gujar et al. 1