Cell cycle plasticity driven by MTOR signaling: integral mechanism for resistance to CDK4/6 inhibition

Pancreatic ductal adenocarcinoma (PDAC), like many KRAS-driven tumors, preferentially loses CDKN2A to bypass the RB tumor suppressive pathway. This finding and a gene expression profile indicative of a CDK4/6-driven cell cycle suggests that PDAC could be particularly sensitive to CDK4/6 inhibition. Analysis of a panel of patient-derived cell lines and xenografts indicates that many pancreatic cancers have an intrinsic resistance to CDK4/6 inhibition that is not due to known molecular mechanisms. Rather, there is a rapid and potent adaptive response that led to the upregulation of Cyclin D1 and Cyclin E proteins and compromised the suppression of a DNA replication gene expression program. These adaptive responses are dependent on MTOR signaling both in cell and animal studies. Strikingly, combination treatments with MTOR and CDK4/6 inhibitor had potent activity across a large number of patient derived models of PDAC underscoring the potential clinical efficacy. Overall design: Patient-derived xenografts from 10 different patient pancreatic cancer tumors were implanted in mice, which were then treated with vehicle control, palbociclib, or with palbociclib in combination with TAK228. RNA sequencing was utilized to define differentially expressed genes. Each model-treatment was sequenced in triplicate.