Small Molecule KRAS Inhibitors: The Future for Targeted Pancreatic Cancer Therapy?
Josef Gillson, Yogambha Ramaswamy, Gurvinder Singh, Alemayehu A. Gorfe, Nick Pavlakis, Jaswinder S. Samra, Anubhav Mittal, Sumit Sahni
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors in the world. Currently, there are no approved targeted therapies for PDAC. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) are known to be a major driver of PDAC progression, but it was considered an undruggable target until recently. Moreover, PDAC also suffers from drug delivery issues due to the highly fibrotic tumor microenvironment. In this perspective, we provide an overview of recent developments in targeting mutant KRAS and strategies to overcome drug delivery issues (e.g., nanoparticle delivery). Overall, we propose that the antitumor effects from novel KRAS inhibitors along with strategies to overcome drug delivery issues could be a new therapeutic way forward in PDAC.