Abstract IA22: Exploiting the heterogeneity of mutant Kras lung tumors to improve therapy

Lung cancer is currently the most lethal cancer worldwide with non-small cell lung carcinoma (NSCLC) accounting for ~85% of all cases. The vast majority of lung cancer patients present with locally advanced, inoperable or metastatic disease and median survival at this stage remains low. Targeted therapies are already improving treatment outcomes, but frequent mutations such as those affecting KRAS (present in ~30% of lung adenocarcinomas, a common subtype of NSCLC) still remain untargetable. Our lab aims to define new vulnerabilities associated with these aggressive and largely therapy-resistant tumors. To achieve this, we are characterizing the mechanisms that drive the malignant progression of mutant Kras lung tumors, using mouse models that closely recapitulate human lung adenocarcinoma. Using a multidisciplinary approach we recently identified distinct genetic, transcriptional and metabolic signatures between low grade and high grade mutant Kras lung tumors. In particular, we showed that high grade mutant Kras lung adenocarcinomas frequently exhibit extra copies of mutant Kras, implying that enhanced mutant Kras activity is positively selected during malignant progression. Moreover, we showed that the gain of just a single mutant copy (single vs double mutant) has a major effect on lung tumour cells in vitro and in vivo, leading to enhanced metastatic potential and metabolic rewiring. In turn, this metabolic rewiring creates unique dependences that can be exploited to selectively target advanced mutant Kras lung tumours. Our work shows that mutant Kras lung tumors are not a single disease, comprising two classes of tumors with mutant Kras allelic content-dependent prognosis and therapeutic susceptibilities. This intrinsic tumor heterogeneity is also present in the human disease and may have contributed to the poor therapeutic responses often associated with mutant KRAS lung tumors in humans. We are currently determining whether this metabolic heterogeneity can be exploited to improve the targeting of human mutant KRAS adenocarcinoma. Citation Format: Carla Martins. Exploiting the heterogeneity of mutant Kras lung tumors to improve therapy [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA22.