RT Journal Article
SR Electronic
T1 Targeting dual signaling pathways in concert with immune checkpoints for the treatment of pancreatic cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 860247
DO 10.1101/860247
A1 Erik S Knudsen
A1 Vishnu Kumarasamy
A1 Sejin Chung
A1 Paris Vail
A1 Stephanie Tzetzo
A1 Amanda Ruiz
A1 Mukund Seshadri
A1 Scott I Abrams
A1 Jianmin Wang
A1 Agnieszka K Witkiewicz
YR 2019
UL http://biorxiv.org/content/early/2019/12/05/860247.abstract
AB Pancreatic cancer harbors a poor prognosis due to the lack of effective systemic therapies. Here we interrogated means to target key effector pathways down-stream from KRAS. We found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumor progression. These effects were associated with stable cell cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors. Together, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumor and host that can contribute to durable control for tumors in combination with immune checkpoint inhibitor therapy.