In a pair of new studies, researchers from Roswell Park Comprehensive Cancer Center outline strategies for overcoming pancreatic cancer’s resistance to treatment through approaches that exploit this cancer’s reliance on uncontrolled, or deregulated, cell proliferation. The companion articles in Oncogene, which is published by the Nature Publishing Group, and Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR), report promising findings from preclinical studies employing existing treatments that have been effective against other solid-tumor cancers.
The study newly published in Oncogene
yesterday reports both new findings about how pancreatic cancer evades the effects of treatment with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors such as palbociclib, ribociclib and abemaciclib and a strategy for overcoming that resistance — by combining CDK4/6 inhibitors with drugs inhibiting another growth promoting kinase MTOR.
“Pancreatic adenocarcinoma is a particularly complex cancer with many different genetic subtypes,” says Agnieszka Witkiewicz, MD
, Director of the Center for Personalized Medicine and Chief of Research in the Department of Pathology at Roswell Park, who is senior author on the Oncogene article. “We demonstrate through our work here that many pancreatic cancers have intrinsic resistance to CDK4/6 inhibition and that we can overcome this resistance by taking advantage of its reliance on the MTOR pathway. Our findings from studies in many different cell lines and preclinical models show that combination treatment with MTOR and CDK4/6 inhibitors can be potent against many distinct types of pancreatic cancer.”
The Clinical Cancer Research
study, published last month, is a proof-of-concept analysis demonstrating that combination treatment with cell cycle checkpoint inhibitors and chemotherapy can be used to overcome the multiple mechanisms of resistance of pancreatic adenocarcinoma tumors.
“For this study, we exploited the replication stress that is known to be evoked by drivers of pancreatic cancer, in particular KRAS
mutations,” says Erik Knudsen, PhD
, Chair of Molecular and Cellular Biology at Roswell Park, who was an author on both studies. “We had to work through multiple unexpected resistance mechanisms of this notoriously recalcitrant cancer type, pancreatic adenocarcinoma, but ultimately were able to show that through coordinated targeting of cell cycle checkpoints with particular chemotherapy combinations you can effectively control pancreatic tumors — which was an exciting and welcome result.”
The Roswell Park team is developing clinical studies to further pursue both approaches.
“We’re quite excited by the prospect of further developing these interventions, particularly in the context of such a hard-to-treat cancer, where new therapeutic options are urgently needed,” adds Dr. Knudsen.
The study in Clinical Cancer Research, “Coordinately targeting cell cycle checkpoint functions in integrated models of pancreatic cancer,” is available at clincancerres.aacrjournals.org
. The Oncogene study is “Cell cycle plasticity driven by MTOR signaling: Integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer,” available at nature.com
. This research was supported in part by two grants from the National Cancer Institute — project no. P30CA016056, Roswell Park’s Cancer Center Support Grant from the NCI, and project no. R01CA211878.