Mechanistic target of rapamycin in the tumor microenvironment and its potential as a therapeutic target for pancreatic cancer

Abstract

Pancreatic cancer(PC) is a devastating disease with a poor prognosis; however, few treatment options are available and the search continues for feasible molecular therapeutic targets, both in the tumor itself and in the tumor microenvironment. The mechanistic target of rapamycin (mTOR) signaling pathway has emerged as an attractive target due to its regulatory role in multiple cellular processes, including metabolism, proliferation, survival, and differentiation, under physiological and pathological conditions. Although mTOR-regulated events in tumor cells and the tumor microenvironment are known to restrict the development and growth of tumor cells, monotherapy with mTOR inhibitors has shown limited efficacy against PC to date, suggesting the need for alternative approaches. In this review, we describe the mechanisms by which mTOR modulates the PC microenvironment and suggest ways its function in immune cells might be exploited for the treatment of PC. We also discuss preclinical and clinical studies with mTOR inhibitors in combination with other therapeutic strategies, most notably immunotherapy. Finally, we highlight the promise that mTOR combinatorial therapy may hold for the treatment of PC in the near future.

Keywords: Combination therapy; Immunotherapy; Mechanistic target of rapamycin; Pancreatic cancer; Tumor microenvironment.