Combination Therapy for Treatment-Resistant Pancreatic Cancer

Graphic- Combination Therapy for Treatment-Resistant Pancreatic Cancer
Inhibiting oncogenic signaling (KRAS→RAF→MEK→ERK) was found to elicit autophagy, a process of cellular recycling that, paradoxically, protects pancreatic ductal carcinoma cells. The discovery led to a new combinatorial approach to pancreatic cancer therapy that involves inhibiting both the MEK pathway and autophagy.


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.

References:

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MAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival. Lee CS, Lee LC, Yuan TL, Chakka S, Fellmann C, Lowe SW, Caplen NJ, McCormick F, Luo J. Proc Natl Acad Sci USA. 2019 Mar 5;116(10):4508-4517.

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Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer.  Bryant KL, Stalnecker CA, Zeitouni D, Klomp JE, Peng S, Tikunov AP, Gunda V, Pierobon M, Waters AM, George SD, Tomar G, Papke B, Hobbs GA, Yan L, Hayes TK, Diehl JN, Goode GD, Chaika NV, Wang Y, Zhang GF, Witkiewicz AK, Knudsen ES, Petricoin EF 3rd, Singh PK, Macdonald JM, Tran NL, Lyssiotis CA, Ying H, Kimmelman AC, Cox AD, Der CJ. Nat Med. 2019 Apr;25(4):628-640.

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Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A, Schuman SS, Shea JE, Seipp MT, Yap JT, Burrell LD, Lum DH, Whisenant JR, Gilcrease GW 3rd, Cavalieri CC, Rehbein KM, Cutler SL, Affolter KE, Welm AL, Welm BE, Scaife CL, Snyder EL, McMahon M. Nat Med. 2019 May;25(5):861.

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U of U Health Key Faculty Collaborators

Conan Kinsey, MD, PhD
Jill Shea, PhD
Jeffrey Yap, PhD
G. Weldon Gilcrease III, MD
Kajsa Affolter, MD
Alana Welm, PhD
Brian Welm, PhD
Courtney Scaife, MD
Eric Snyder, MD, PhD