Abstract IA11: The use of GEM tumor models to identify effective therapies against KRAS mutant tumors

KRAS oncogenes are responsible for one fourth of all human tumors, including lung and pancreatic adenocarcinomas, two tumor types with some of the worse prognoses. Unfortunately, development of suitable therapies to treat these tumors has remained elusive for the last 35 years. Although KRAS remains an undruggable target (with the possible exception of the KRASG12C isoform), most of its downstream effectors are druggable kinases. Indeed, pharma and biotech companies have already developed dozens of selective inhibitors against these kinases. Yet none of them has been approved by the FDA, mostly due to unacceptable toxicities at antitumor effective doses. Hence, patients are still treated with old chemotherapy drugs. To address this important health issue, we have used a new generation of genetically engineered mouse (GEM) tumor models of KRas/Tp53 driven lung and pancreatic tumors to deconstruct oncogenic KRas signaling to identify those effectors whose systemic ablation/inactivation in tumor-bearing mice will result in therapeutic responses without inducing unacceptable toxicities. We have used this experimental strategy to interrogate the effect of ablating/inactivating each of the members of the MAPK cascade, including the Raf, Mek, and Erk kinases, as well as key effectors of the PI3K pathway, including PI3K p110alpha and mTOR. We have also evaluated additional downstream signaling elements such as the cell cycle Cdks. This systematic approach has revealed that most of the KRas signaling effectors are not suitable therapeutic targets due to either lack of therapeutic activity, such as Cdk2, Cdk6 A-Raf, or B-Raf, or to the induction of unacceptable toxicities such as the Mek1/2 and Erk1/2 kinases, PI3K p110alpha, mTOR, and Cdk1. Only Raf1 and Cdk4 turned out to be suitable therapeutic targets, based not only on their antitumor properties but also on the well-tolerated toxicities. Surprisingly, EGFR, an upstream effect of KRas, also has suitable therapeutic activity in pancreatic but not in lung tumors. We are now combining these targets to define more efficacious therapeutic strategies that could be eventually translated to the clinic. Moreover, we are using these experimental GEM tumor models to identify potential resistance mechanisms to these therapies. Citation Format: Mariano Barbacid. The use of GEM tumor models to identify effective therapies against KRAS mutant tumors [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA11.