Friday, May 9, 2025
5/9/2025
Targeting SMARCA2 to overcome resistance of SMARCA4-mutant lung cancer to KRAS G12C inhibitors - Project summary Lung cancer is a devastating disease that remains the top cause of cancer mortality. Despite improvements in targeted therapies against oncogenic kinases and immunotherapies for select patients, the majority of patients with lung cancer still lack effective therapeutics, underscoring the dire need for additional treatment approaches. Recent discovery of KRASG12C inhibitors (KRASG12Ci) has generated tremendous excitement and hope. Unfortunately, the duration of response to KRASG12Ci is very short with progression free survival of only 6-7 months due to primary and adaptive resistance. Further, a recent clinical observation showed that co-mutations in the tumor suppressor gene SMARCA4 predict even poorer response to KRASG12Ci, further increasing the urgency to understand and overcome resistance in this context. We have recently corroborated these clinical observations by various experimental approaches. As SMARCA2 is a known synthetic lethal genetic interaction partner to SMARCA4, we sought to study whether targeting SMARCA2 is a possible strategy to overcome resistance of SMARCA4 and KRAS co-mutant cells to KRASG12Ci. To this end, we have developed small molecules that degrade SMARCA2 based on PROTAC (proteolysis targeting chimera) technology. Our data indicates that SMARCA2 PROTACs, including our lead molecule YD23, induce robust SMARCA2 degradation, show promising combination effect with KRASG12Ci and are excellent chemical tools to determine the therapeutic potential of SMARCA2 targeting. In this proposal we first aim to investigate the mechanism of resistance of SMARCA4 mutant lung cancer to KRASG12Ci. We intend to utilize several orthogonal, genetically well-defined model systems and perform in depth molecular characterizations including unbiased transcriptomic, chromatin accessibility and SMARCA2/4 CUT&RUN to identify direct targets of SMARCA2/4 that are modulated by sotorasib, a prototypical KRASG12Ci. We also intend to experimentally develop cell lines resistant to the combination of YD23 and sotorasib that should help in understanding potential mechanisms of drug resistance that are expected in the future if used in patients. To aid our understanding of potential side effects of combination of YD23 and sotorasib, we aim to perform tolerability studies in mice. Importantly, we will determine the anti-tumor efficacy of YD23 and sotorasib using established lung cancer xenografts and novel PDX models. Finally, we will determine gene expression changes within tumors upon YD23, sotorasib as single agent or in combination to elucidate the molecular alterations underlying the in vivo biological effects of our novel combination strategy. In conclusion, these experiments are expected to elaborate the mechanism of resistance of SMARCA4 mutant lung cancer to KRASG12Ci and determine the potential utility of SMARCA2 PROTACs to overcome this resistance. Finally, as KRAS inhibitors are rapidly evolving beyond G12C into other genotypes, our work could have broader ramifications against multiple other cancer types.
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