Reference Detail

Ref Type

Journal Article

PMID

(30833748)

Authors

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, Cavalieri CC, Rehbein KM, Cutler SL, Affolter KE, Welm AL, Welm BE, Scaife CL, Snyder EL, McMahon M

Title

Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature medicine	25	4	2019 04	620-627	Nat Med

URL

Abstract Text

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, KRAS1-4. 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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS Q61R	melanoma	sensitive	Chloroquine + Trametinib	Preclinical - Pdx	Actionable	In a preclinical study, combination treatment with Mekinist (trametinib) and Chloroquine resulted in tumor regression in a melanoma patient-derived xenograft (PDX) model harboring NRAS Q61R (PMID: 30833748).	30833748
NRAS mutant	melanoma	sensitive	Chloroquine + Trametinib	Preclinical - Pdx	Actionable	In a preclinical study, combination treatment with Mekinist (trametinib) and Chloroquine resulted in tumor regression in a melanoma patient-derived xenograft (PDX) model harboring an NRAS mutation (PMID: 30833748).	30833748
BRAF V600E	colorectal cancer	sensitive	Chloroquine + Trametinib	Preclinical - Pdx	Actionable	In a preclinical study, combination treatment with Mekinist (trametinib) and Chloroquine resulted in tumor regression in a colorectal cancer patient-derived xenograft (PDX) model harboring BRAF V600E (PMID: 30833748).	30833748