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 study, published in Oncogene 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,” said Agnieszka Witkiewicz, senior author of this 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 additional study, published in Clinical Cancer Research 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 tumours.

“For this study, we exploited the replication stress that is known to be evoked by drivers of pancreatic cancer, in particular KRAS mutations,” said Erik Knudsen, 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 tumours - which was an exciting and welcome result.”

The Roswell Park team are 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,” Dr Knudsen added. 

Source: Roswell Park