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Ref Type Journal Article
PMID (32371478)
Authors Gstalder C, Liu D, Miao D, Lutterbach B, DeVine AL, Lin C, Shettigar M, Pancholi P, Buchbinder EI, Carter SL, Manos MP, Rojas-Rudilla V, Brennick R, Gjini E, Chen PH, Lako A, Rodig S, Yoon CH, Freeman GJ, Barbie DA, Hodi FS, Miles W, Van Allen EM, Haq R
Title Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade.
Journal Cancer discovery
Vol 10
Issue 9
Date 2020 Sep
URL
Abstract Text The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti-PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti-PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG1, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7-deficient cells was sufficient to sensitize them to anti-PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy. SIGNIFICANCE: Our findings establish a role of the commonly inactivated tumor suppressor FBXW7 as a genomic driver of response to anti-PD-1 therapy. Fbxw7 loss promotes resistance to anti-PD-1 through the downregulation of viral sensing pathways, suggesting that therapeutic reactivation of these pathways could improve clinical responses to checkpoint inhibitors in genomically defined cancer patient populations.This article is highlighted in the In This Issue feature, p. 1241.

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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
FBXW7 loss colon cancer predicted - resistant unspecified PD-1 antibody Preclinical Actionable In a preclinical study, an FBXW7-deficient colon cancer cell line in a mouse model was resistant to treatment with an unspecified PD-1 antibody, demonstrating poor survival and decreased inhibition of tumor growth compared to models with wild-type FBXW7 (PMID: 32371478). 32371478
FBXW7 R505C melanoma predicted - resistant Pembrolizumab Case Reports/Case Series Actionable In a clinical case study, a melanoma patient treated with Keytruda (pembrolizumab) demonstrated a response in all lesions except one, which was found to harbor FBXW7 R505C (PMID: 32371478). 32371478
FBXW7 R505C melanoma predicted - resistant unspecified PD-1 antibody Preclinical Actionable In a preclinical study, a melanoma cell line expressing FBXW7 R505C in a mouse model conferred resistance to treatment with an unspecified PD-1 antibody, demonstrating increased tumor volume and decreased survival compared to models with wild-type FBXW7 (PMID: 32371478). 32371478
FBXW7 loss melanoma predicted - resistant unspecified PD-1 antibody Preclinical Actionable In a preclinical study, an FBXW7-deficient melanoma cell line in a mouse model was resistant to treatment with an unspecified PD-1 antibody, demonstrating increased tumor volume and poor survival compared to models with wild-type FBXW7 (PMID: 32371478). 32371478