Reference Detail

Ref Type

Journal Article

PMID

(27433843)

Authors

Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, Sandoval S, Barthly L, Saco J, Homet Moreno B, Mezzadra R, Chmielowski B, Ruchalski K, Shintaku IP, Sanchez PJ, Puig-Saus C, Cherry G, Seja E, Kong X, Pang J, Berent-Maoz B, Comin-Anduix B, Graeber TG, Tumeh PC, Schumacher TN, Lo RS, Ribas A

Title

Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The New England journal of medicine	375	9	2016 Sep 01	819-29	N Engl J Med

URL

Abstract Text

Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later.Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
B2M	NCBI	AMYLD6\|IMD43\|MHC1D4		B2M, beta-2-microglobulin, forms the light chain of the class I major histocompatibility complex (MHC) (PMID: 3312414) and is required for antigen presentation during the immune response (PMID: 27433843). B2M loss of function mutations have been associated with mismatch repair (MMR) deficiency in colon cancer (PMID: 28616688) and with acquired resistance to immune checkpoint inhibitors in melanoma (PMID: 27433843, PMID: 30466478).	Tumor suppressor

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
B2M	S14fs	frameshift	loss of function	B2M S14fs results in a change in the amino acid sequence of the B2m protein beginning at aa 14 of 119, likely resulting in premature truncation of the functional protein (UniProt.org). S14fs confers a loss of function to the B2m protein as demonstrated by lack of MHC class I membrane localization (PMID: 27433843, PMID: 29070816).	Y
JAK1	Q503*	nonsense	loss of function - predicted	JAK1 Q503* results in a premature truncation of the Jak1 protein at amino acid 503 of 1154 (UniProt.org). Q503* is associated with resistance to immunotherapy (PMID: 27433843), but due to the loss of the protein kinase domains (UniProt.org), is predicted to lead to a loss of Jak1 protein function.	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
B2M S14fs	melanoma	predicted - resistant	Pembrolizumab	Case Reports/Case Series	Actionable	In a clinical study, a melanoma patient treated with Keytruda (pembrolizumab) initially demonstrated a partial response, however, post 453 days, developed disease progression likely due to the secondary resistance mutation, B2M S14fs (PMID: 27433843).	27433843
JAK1 Q503*	melanoma	predicted - resistant	Pembrolizumab	Case Reports/Case Series	Actionable	In a clinical study, a melanoma patient treated with Keytruda (pembrolizumab) initially demonstrated a partial response, however, post 419 days developed disease progression likely due to the secondary resistance mutation, JAK1 Q503* (PMID: 27433843).	27433843
JAK2 inact mut	melanoma	predicted - resistant	Pembrolizumab	Case Reports/Case Series	Actionable	In a clinical study, a melanoma patient treated with Keytruda (pembrolizumab) initially demonstrated a partial response, however, post 734 days developed disease progression due to a splice site mutation in JAK2, which resulted in an intron inclusion and an early stop codon, leading to a loss of protein expression (PMID: 27433843).	27433843