Reference Detail

Ref Type

Journal Article

PMID

(25665005)

Authors

Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E, Asthana S, Neel D, Yan JJ, Lu X, Pham L, Wang MM, Karachaliou N, Cao MG, Manzano JL, Ramirez JL, Torres JM, Buttitta F, Rudin CM, Collisson EA, Algazi A, Robinson E, Osman I, Muñoz-Couselo E, Cortes J, Frederick DT, Cooper ZA, McMahon M, Marchetti A, Rosell R, Flaherty KT, Wargo JA, Bivona TG

Title

The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature genetics	47	3	2015 Mar	250-6	Nat Genet

URL

Abstract Text

Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.

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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
BRAF V600E	colon cancer	sensitive	Navitoclax + Vemurafenib	Preclinical	Actionable	In a preclinical study, Navitoclax (ABT-263) enhanced the inhibitory effect of Zelboraf (vemurafenib) on human colon cancer cells harboring BRAF V600E in culture (PMID: 25665005).	25665005
BRAF V600E	colon cancer	sensitive	Navitoclax + Trametinib	Preclinical	Actionable	In a preclinical study, Navitoclax (ABT-263) enhanced the inhibitory effect of Mekinist (trametinib) on human colon cancer cells harboring BRAF V600E in culture (PMID: 25665005).	25665005
BRAF V600E	lung non-small cell carcinoma	sensitive	TW-37 + Vemurafenib	Preclinical	Actionable	In a preclinical study, TW-37 enhanced the inhibitory effect of Zelboraf (vemurafenib) on human non-small cell lung cancer cells harboring BRAF V600E in culture (PMID: 25665005).	25665005
BRAF V600E	lung non-small cell carcinoma	sensitive	Navitoclax + Trametinib	Preclinical	Actionable	In a preclinical study, Navitoclax (ABT-263) enhanced the inhibitory effect of Mekinist (trametinib) on human non-small cell lung cancer cells harboring BRAF V600E in culture (PMID: 25665005).	25665005
BRAF V600E	lung non-small cell carcinoma	sensitive	Navitoclax + Vemurafenib	Preclinical	Actionable	In a preclinical study, Navitoclax (ABT-263) enhanced the inhibitory effect of Zelboraf (vemurafenib) on human non-small cell lung cancer cells harboring BRAF V600E in culture (PMID: 25665005).	25665005
BRAF V600E	melanoma	sensitive	Trametinib + TW-37	Preclinical	Actionable	In a preclinical study, TW-37 enhanced the inhibitory effect of Mekinist (trametinib) on human melanoma cells harboring BRAF V600E in culture (PMID: 25665005).	25665005
BRAF V600E	melanoma	sensitive	Navitoclax + Vemurafenib	Preclinical	Actionable	In a preclinical study, Navitoclax (ABT-263) enhanced the inhibitory effect of Zelboraf (vemurafenib) on human melanoma cells harboring BRAF V600E in culture (PMID: 25665005).	25665005
BRAF V600E	melanoma	sensitive	TW-37 + Vemurafenib	Preclinical	Actionable	In a preclinical study, TW-37 enhanced the inhibitory effect of Zelboraf (vemurafenib) on human melanoma cells harboring BRAF V600E in culture (PMID: 25665005).	25665005
BRAF V600E	lung non-small cell carcinoma	sensitive	Trametinib + TW-37	Preclinical	Actionable	In a preclinical study, TW-37 enhanced the inhibitory effect of Mekinist (trametinib) on human non-small cell lung cancer cells harboring BRAF V600E in culture (PMID: 25665005).	25665005
BRAF V600E	melanoma	sensitive	Navitoclax + Trametinib	Preclinical	Actionable	In a preclinical study, Navitoclax (ABT-263) enhanced the inhibitory effect of Mekinist (trametinib) on human melanoma cells harboring BRAF V600E in culture (PMID: 25665005).	25665005