KRASG12V Degraders Provide a Potential Therapeutic Opportunity in Lung Adenocarcinoma

Mutant KRAS inhibition has revolutionized the treatment of lung adenocarcinoma. Unfortunately, responses to this form of targeted therapy are often of limited duration because of the development of resistance. Targeted protein degradation, including using PROTACs (PROteolysis-TArgeting Chimeras), presents an alternative approach to targeting oncogenic drivers in cancer. In this issue of Cancer Research, Martín and colleagues developed a dTAG-KRASG12V syngeneic mouse model that allows for the study of the effects of degrading the KRASG12V oncoprotein in vivo. The authors discovered that degrading the KRASG12V oncoprotein leads to regression of the resulting lung adenocarcinoma tumors. Most of the regression was based on cancer cell-intrinsic responses, although the tumor microenvironment also underwent substantial remodeling. Despite the initial efficacy of the treatment, the authors found that prolonged PROTAC KRAS degrader treatment eventually resulted in relapse. Resistance to PROTAC treatment seemed to be driven by dysregulation of the ubiquitin-proteasome system that is required for the activity of the PROTAC degraders. Despite developing resistance to the PROTAC degraders, the resulting tumors were still dependent on the KRAS oncoprotein, meaning that they were still sensitive to conventional KRAS inhibitors. Thus, PROTACs that degrade the KRAS oncoprotein are a promising modality for the treatment of lung adenocarcinomas. Resistance to PROTACs may differ from conventional KRAS inhibitors, suggesting potential strategies for overcoming such resistance. See related article by Martín et al., p. 4115.