Roswell Park Team Proposes Strategy for Making Pancreatic Tumors Respond to Checkpoint Inhibition

New study provides rationale for combining targeted therapies with anti-PD-L1 immunotherapy

BUFFALO, N.Y. — A possible new strategy for treating pancreatic cancer highlights the promise of collaboration between experts in both precision medicine and immunology. The findings from a team led by Agnieszka Witkiewicz, MD, and Erik Knudsen, PhD, at Roswell Park Comprehensive Cancer Center and published today in the journal Gut suggest a combination treatment approach that can make some breakthrough immunotherapy drugs effective for more patients with pancreatic cancer. The study opens up a possibility for improving outcomes for patients with a notoriously difficult-to-treat cancer using a combination of existing drugs.   

While most pancreatic cancers have been invulnerable to immune checkpoint inhibitors such as nivolumab (Opdivo) and pembrolizumab (Keytruda), this team has uncovered an opportunity to convert many pancreatic tumors to be sensitive to these anti-PD-L1 agents. The combination of CDK4/6 inhibitors and MEK inhibitors, they report, worked together to slow the growth of pancreatic cancer tumors in preclinical cancer models.

“We found that a combined targeting of signaling pathways could elicit sensitivity to anti-PD-L1 therapy in immune-competent models, supporting the use of MEK and CDK4/6 inhibitors to change the tumor microenvironment and, ultimately, achieve sensitivity to immune checkpoint inhibitors,” says Dr. Witkiewicz, who is Director of the Center for Personalized Medicine at Roswell Park.

CDK4/6 inhibitors such as abemaciclib (Verzenio), palbociclib (Ibrance) and ribociclib (Kisqali) have previously been approved for use in patients with

estrogen-responsive (ER+) breast cancers, and MEK inhibitors have been used in patients with certain kinds of melanomas. Both had previously been provided to pancreatic cancer patients, separately, but had proven ineffective.

The new publication reports that MEK inhibitors can cooperate with CDK4/6 inhibitors to limit cell-cycle plasticity and invoke stable cell-cycle arrest in patient-derived models of pancreatic cancer. This combination also induces interferon responses and antigen presentations in tumor cells that make tumors more susceptible to immunotherapy.  

The study employed a diverse array of state-of-the-art, clinically relevant methods, including magnetic resonance imaging (MRI), multi-spectral imaging and single-cell sequencing technologies accessible through the Center for Personalized Medicine and associated Genomics Shared Resource at Roswell Park — advanced technologies that are important tools for integrating the effects of therapies on both the tumor and the immune system. The work resulted from collaboration across Roswell Park’s Personalized Medicine, Immunology, Oral Oncology and Biostatistics and Bioinformatics teams.

“Targeting both the cancer cells using these pathway-specific inhibitors and the immune system led to an innovative regimen that rendered pancreatic cancer, typically resistant to death, now prone to significant growth inhibition,” says Scott Abrams, PhD, Co-Leader of Roswell Park’s Tumor Immunology and Immunotherapy Program and co-author on this study. “This discovery adds to the arsenal of potential weapons needed to combat such a devastating disease.”

While more research is needed, this proof-of-concept study supports assessing the combined use of MEK and CDK4/6 inhibitors in clinical trials in patients with pancreatic cancer which are being planned at Roswell Park Comprehensive Cancer Center.    

Additional co-authors include Roswell Park faculty leaders Mukund Seshadri, DDS, PhD, and Jianmin Wang, PhD, as well as collaborators from the University of Arizona Cancer Center.

This work was supported in part by grants from the National Cancer Institute (project nos. P30CA016056 and CA211878).