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Ref Type Journal Article
PMID (33593882)
Authors Nguyen TT, Ramsay L, Ahanfeshar-Adams M, Lajoie M, Schadendorf D, Alain T, Watson IR
Title Mutations in the IFNγ-JAK-STAT Pathway Causing Resistance to Immune Checkpoint Inhibitors in Melanoma Increase Sensitivity to Oncolytic Virus Treatment.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 27
Issue 12
Date 2021 Jun 15
URL
Abstract Text Next-generation sequencing studies and CRISPR-Cas9 screens have established mutations in the IFNγ-JAK-STAT pathway as an immune checkpoint inhibitor (ICI) resistance mechanism in a subset of patients with melanoma. We hypothesized ICI resistance mutations in the IFNγ pathway would simultaneously render melanomas susceptible to oncolytic virus (OV) therapy.Cytotoxicity experiments were performed with a number of OVs on a matched melanoma cell line pair generated from a baseline biopsy and a progressing lesion with complete JAK2 loss from a patient that relapsed on anti-PD-1 therapy, in melanoma lines following JAK1/2 RNA interference (RNAi) and pharmacologic inhibition and in Jak2 knockout (KO) B16-F10 mouse melanomas. Furthermore, we estimated the frequency of genetic alterations in the IFNγ-JAK-STAT pathway in human melanomas.The melanoma line from an anti-PD-1 progressing lesion was 7- and 22-fold more sensitive to the modified OVs, herpes simplex virus 1 (HSV1-dICP0) and vesicular stomatitis virus (VSV-Δ51), respectively, compared with the line from the baseline biopsy. RNAi, JAK1/2 inhibitor studies, and in vivo studies of Jak2 KOs B16-F10 melanomas revealed a significant increase in VSV-Δ51 sensitivity with JAK/STAT pathway inhibition. Our analysis of The Cancer Genome Atlas data estimated that approximately 11% of ICI-naïve cutaneous melanomas have alterations in IFNγ pathway genes that may confer OV susceptibility.We provide mechanistic support for the use of OVs as a precision medicine strategy for both salvage therapy in ICI-resistant and first-line treatment in melanomas with IFNγ-JAK-STAT pathway mutations. Our study also supports JAK inhibitor-OV combination therapy for treatment-naïve melanomas without IFN signaling defects.See related commentary by Kaufman, p. 3278.

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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
HSV1-dICP0 HSV1-dICP0 is an oncolytic herpes simplex virus type 1 with deletion of the ICP0 gene, which may induce a cytotoxic response in tumor cells (PMID: 33593882).
VSV-delta51 VSV(M Delta 51) VSV-delta51 is an oncolytic vesicular stomatitis virus (VSV) with a deletion of methionine 51 in the M protein, which may induce a cytotoxic response in tumor cells and an antitumor immune response (PMID: 14585354, PMID: 33593882).
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
JAK2 LOH JAK2 inact mut melanoma predicted - sensitive HSV1-dICP0 Preclinical - Patient cell culture Actionable In a preclinical study, a melanoma patient-derived cell line harboring an inactivating JAK2 mutation and JAK2 loss of heterozygosity resulted in sensitivity to treatment with an oncolytic virus, HSV-dICP0, in culture (PMID: 33593882). 33593882
JAK2 dec exp melanoma predicted - sensitive VSV-delta51 Preclinical - Cell culture Actionable In a preclinical study, siRNA knockdown of JAK2 in a melanoma cell line resulted in increased sensitivity to treatment with an oncolytic virus, VSV-delta51, in culture (PMID: 33593882). 33593882
JAK1 dec exp melanoma predicted - sensitive VSV-delta51 Preclinical - Cell culture Actionable In a preclinical study, siRNA knockdown of JAK1 in a melanoma cell line resulted in increased sensitivity to treatment with an oncolytic virus, VSV-delta51, in culture (PMID: 33593882). 33593882
JAK2 loss melanoma sensitive VSV-delta51 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with VSV-delta51 resulted in decreased cell viability in melanoma cell lines with a loss of JAK2 in culture, and resulted in an increased median survival in a syngeneic mouse model grafted with a CRISPR-mediated JAK2 knockout melanoma cell line (PMID: 33593882). 33593882
JAK2 LOH JAK2 inact mut melanoma predicted - sensitive VSV-delta51 Preclinical - Patient cell culture Actionable In a preclinical study, a melanoma patient-derived cell line harboring an inactivating JAK2 mutation and JAK2 loss of heterozygosity resulted in sensitivity to treatment with an oncolytic virus, VSV-delta51, in culture (PMID: 33593882). 33593882