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Pancreas
Original research
Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer
  1. Erik S Knudsen1,2,
  2. Vishnu Kumarasamy1,2,
  3. Sejin Chung1,2,
  4. Amanda Ruiz3,
  5. Paris Vail1,2,
  6. Stephanie Tzetzo4,
  7. Jin Wu1,
  8. Ram Nambiar1,
  9. Jared Sivinski3,
  10. Shailender S Chauhan3,
  11. Mukund Seshadri5,
  12. Scott I Abrams4,
  13. Jianmin Wang6,
  14. Agnieszka K Witkiewicz1,7
  1. 1 Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
  2. 2 Molecular & Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
  3. 3 Cancer Center, University of Arizona, Tucson, Arizona, USA
  4. 4 Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
  5. 5 Oral Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
  6. 6 Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
  7. 7 Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
  1. Correspondence to Erik S Knudsen, Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA; erik.knudsen{at}roswellpark.org; Dr Agnieszka K Witkiewicz, Center for Precision Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA; Agnieszka.Witkiewicz{at}roswellpark.org

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.

  • pancreatic cancer
  • immunotherapy
  • cancer genetics
  • cell cycle

https://doi.org/10.1136/gutjnl-2020-321000

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    Footnotes

    • Correction notice This article has been corrected since it published Online First. Authors Jared Sivinski and Shailender S Chauhan have been added and the text line 'The vehicle and palbociclib control data for these PDX models has been reported.' has been added in the first paragraph of the 'Mice and patient-derived xenografts' section.

    • Contributors All authors contributed to the manuscript. Roles are specified by their initials. Conception or design of the work: EK, AKW, SIA, MS and JW; acquisition, analysis or interpretation of data: VK, SC, PV, RN, ST, JW, AR, JW, EK, AKW and SIA. Drafting the work or revising it critically for important intellectual content: EK, AKW, SIA, PV, JW and VK. Final approval of the version published: all authors. Funding: EK and AKW.

    • Funding CA211878 from the National Institutes of Health.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request. The gene expression data in this manuscript will be made available through Gene Expression Omnibus under the title of the manuscript. Any other primary data will be made available upon reasonable request.

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