Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

Erik Knudsen, Vishnu Kumarasamy, Sejin Chung, Amanda Ruiz, Paris Vail, Stephanie Tzetzo, Jin Wu, Ram Nambiar, Mukund Seshadri, Scott I. Abrams, Jianmin Wang, Agnieszka K. Witkiewicz

Research output: Contribution to journalArticle

Abstract

Objective: This study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer. Design: Patient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic syngeneic models. Single-cell RNA sequencing and multispectral imaging were employed to delineate effects on the immunological milieu in the tumour microenvironment. Results: We found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumour 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. Conclusions: Together, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumour and immune microenvironment. This combination-targeted treatment can promote robust tumour control in combination with immune checkpoint inhibitor therapy.

Original languageEnglish (US)
JournalGut
DOIs
StateAccepted/In press - 2020
Externally publishedYes

Keywords

  • cancer genetics
  • cell cycle
  • immunotherapy
  • pancreatic cancer

ASJC Scopus subject areas

  • Gastroenterology

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    Knudsen, E., Kumarasamy, V., Chung, S., Ruiz, A., Vail, P., Tzetzo, S., Wu, J., Nambiar, R., Seshadri, M., Abrams, S. I., Wang, J., & Witkiewicz, A. K. (Accepted/In press). Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer. Gut. https://doi.org/10.1136/gutjnl-2020-321000