Lung cancer is the leading cause of cancer-related deaths worldwide. KRAS is the most frequent mutated driver gen in non-small cell lung cancer (NSCLC). Nevertheless, KRAS has been recognized as undruggable for many years. KRASG12C inhibitors are being developed in clinical trials and have revealed promising results in lung cancer patients. While these therapies hold great promise, they face the same limitation as other targeted therapies, the therapeutic potential of these inhibitors can be impaired by resistance mechanisms. Deciphering resistance mechanisms to KRASG12Ci is of prime relevance to predict which patients may benefit from these therapies. And exploring resistance-overcoming therapeutic strategies is essential for improving precision oncology in KRAS-driven cancer.
We generated resistant cell lines to KRASG12C inhibitors, exposing cells to increasing concentrations of drugs until they were resistant to the drug. Once the resistant cell lines were generated, protein was extracted to characterize the resistant cell lines using phospho-arrays and Western Blot techniques. In addition, the DNA and RNA from parental and resistant cell lines were extracted and sequenced by NGS to look for transcriptomic and genomic differences. With all these data we identified some molecular alterations that may be responsible for the acquired resistance and explored some resistance-overcoming therapeutic strategies.
We generated 11 Sotorasib- or Adagrasib-resistant cell lines and we characterized them at the proteomic, transcriptomic and genomic level. Using proteomic characterization, we observed differences in the expression and/or activation of some receptors, such as EGFR and FGFR, in many resistant cell lines. And using the transcriptomic and genomic data we found some alterations that also could explain the acquired resistances. Then, we explored some resistance-overcoming therapeutic strategies in vitro and in vivo, which have shown promising results.
1) We have found different mechanisms of acquired resistance to KRASG12Ci using proteomic, transcriptomic and genomic data. 2) We have found some effective resistance-overcoming therapeutic strategies in vitro and in vivo.
The authors.
Instituto de Salud Carlos III (PI19/00320).
L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, Beigene, Daiichi Sankyo, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme Corp., BMS, Janssen-Cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Other, Member: AACR, ASCO, ESMO; Financial Interests, Personal, Other, Foundation Board Member: AECC; Financial Interests, Personal, Other, President. V CASEICA (Spanish Association of Cancer Research): ASEICA; Financial Interests, Personal, Other, Foundation president: ONCOSUR; Financial Interests, Personal, Other, member: Small Lung Cancer Group. All other authors have declared no conflicts of interest.