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Pathway Defects in Acquired Resistance to PD-1 Inhibition in Melanoma Identified

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Key Points

  • Mutations in interferon-receptor–associated JAK1 or JAK2 were found in two patients with acquired resistance to PD-1 inhibition in melanoma.
  • A mutation in B2M resulting in loss-of-surface expression of major histocompatibility complex class I was found in one patient.

In a study reported in The New England Journal of Medicine, Zaretsky et al found that defects in interferon receptor signaling and antigen-presenting pathways were associated with acquired resistance to PD-1 (programmed cell death protein 1) inhibition in melanoma.

Resistance Mutations Identified

The study involved analysis of paired baseline and relapsing lesion biopsy samples in four patients with metastatic melanoma who had initial tumor regression on pembrolizumab (Keytruda) followed by disease progression after months to years.

Whole-exome sequencing showed clonal selection and outgrowth of the acquired resistant tumors. In two patients, resistance-associated loss-of-function mutations in genes for interferon receptor–associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2) were identified, concurrent with loss of the wild-type allele. In a third patient, a truncating mutation in the gene for the antigen-presenting protein beta-2-microglobulin (B2M) was identified. The JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon-gamma and loss of its antiproliferative effects, and the B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.

The investigators concluded: “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.”

The study was funded by the National Institutes of Health and others.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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