Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas

KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.

Automated summary

KRASG12C inhibitors have greatly improved the clinical management of KRASG12C-mutant lung adenocarcinoma patients, but resistance develops rapidly. In this study, genetically engineered mice were used to compare the efficacy and resistance between genetic ablation and pharmacological inhibition of mutant Kras. Results showed that Kras ablation effectively regressed tumors and prevented resistant cells, while treatment with sotorasib, a selective KRASG12C inhibitor, led to limited antitumor response and rapid onset of resistance. Unlike human tumors, resistance in mice was not due to mutations in RAS signaling pathways, but rather amplification of mutant Kras allele and activation of xenobiotic metabolism pathways.