Combination Therapy for Treatment-Resistant Pancreatic Cancer

Kinsey and colleagues reported that inhibition of oncogenic KRAS→RAF→MEK→ERK signaling elicited autophagy, a process of cellular recycling that paradoxically protects pancreatic ductal carcinoma cells from the cytotoxic effects of KRAS pathway inhibition. Inhibition of MEK has been shown to activate the LKB1→AMPK→ULK1 signaling axis, a key regulator of autophagy. Based on these observations, McMahon and colleagues reported that simultaneous combined inhibition of MEK plus autophagy displayed synergistic anti-proliferative effects against cultured pancreatic cancer cell lines and promoted regression of xenografted patient-derived pancreatic tumors in mice. Furthermore, xenografts of patient-derived NRAS-mutated melanoma or BRAF-mutated colorectal cancer displayed similarly enhanced responses. Finally, treatment of a pancreatic cancer patient with the combination of trametinib (MEK1/2 inhibitor) plus hydroxychloroquine (autophagy inhibitor) resulted in a partial, but nonetheless striking, disease response. The novelty is the discovery of the contingent dependence of RAS-, or BRAF-mutated tumors, including melanoma, colorectal and pancreatic cancer, on the autophagy pathway. This work suggests that this combination therapy represents a novel strategy to target RAS (oncoprotein)-driven cancers and has led to multiple ongoing clinical trials.