Pancreatic ductal adenocarcinoma (PDA) was responsible for ~ 44,000 deaths in the United States in 2018 and is the epitome of a recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS1,2,3,4. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis5. However, paradoxically, inhibition of this pathway has provided no clinical benefit to patients with PDA6. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling elicits autophagy, a process of cellular recycling that protects PDA cells from the cytotoxic effects of KRAS pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of the LKB1→AMPK→ULK1 signaling axis, a key regulator of autophagy. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro and promotes regression of xenografted patient-derived PDA tumors in mice. The observed effect of combination trametinib plus chloroquine was not restricted to PDA as other tumors, including patient-derived xenografts (PDX) of NRAS-mutated melanoma and BRAF-mutated colorectal cancer displayed similar responses. Finally, treatment of a patient with PDA with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers.
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The data that support the findings of this study are available from the corresponding author upon request.
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We dedicate this work to the memory of our patient and his family, whose courage continues to inspire us to further improve the diagnosis and treatment of pancreatic cancer. We thank the members of the McMahon Lab for their support, advice, guidance, comments and discussions during the course of this work. Additionally we thank I. Garrido-Laguna (HCI/Univ. of Utah), M. Tempero, E. Collisson and F. McCormick (U.C. San Francisco), E. White (Rutgers University), D. Tuveson (Cold Spring Harbor), and K. Olive (Columbia) for advice and guidance, J. Mulcahy-Levy and A. Thorburn (U.C. Denver) for inspiration, advice, guidance and reagents, H. Land (University of Rochester Medical Center) and K. Shokat (UCSF) for providing reagents, NCI Patient-Derived Models Repository for supplying the NCI-516677 NRAS-mutated melanoma PDX, K. Owings, D. Lum and the HCI Preclinical Research Resource for assistance with tumor xenografts and drug treatments and M. Silvis for assistance with drug dosing. C.K. & M.M. wish to acknowledge the collegiality of K. Bryant and C. Der (University of North Carolina, Chapel Hill) for ongoing discussions and for sharing data in advance of publication. M.M. acknowledges financial support from the National Cancer Institute (R01-CA176839, R01-CA131261 & P30-CA042014), the Pancreatic Cancer Collective, Melanoma Research Alliance, Five for the Fight, and the Huntsman Cancer Foundation. E.L.S. was supported in part by a Career Award for Medical Scientists from the Burroughs Wellcome Fund, a V Scholar Award, the Huntsman Cancer Foundation, and the NIH (R01CA212415). B.E.W. acknowledges support from the National Cancer Institute and DoD (U54CA224076 and W81XWH1410417). A.L.W. acknowledges support from the Huntsman Cancer Foundation. C.G.K acknowledges support from the Huntsman Cancer Foundation. A.M.B. acknowledges support from Fondation pour la Recherché Medicale (FDM20150633361) and Societe Francaise de Dermatologie.