Current insights into combination therapies with MAPK inhibitors and immune checkpoint blockade

Min Hwa Shin, Jiyoung Kim, Siyoung A. Lim, Jeongsoo Kim, Kyung Mi Lee

Research output: Contribution to journalReview article

2 Citations (Scopus)

Abstract

The recent development of high-throughput genomics has revolutionized personalized medicine by identifying key pathways and molecular targets controlling tumor progression and survival. Mitogen-activated protein kinase (MAPK) pathways are examples of such targets, and inhibitors against these pathways have shown promising clinical responses in patients with melanoma, non-small-cell lung cancer, colorectal cancer, pancreatic cancer, and thyroid cancer. Although MAPK pathway-targeted therapies have resulted in significant clinical responses in a large proportion of cancer patients, the rate of tumor recurrence is high due to the development of resistance. Conversely, immunotherapies have shown limited clinical responses, but have led to durable tumor regression in patients, and complete responses. Recent evidence indicates that MAPK-targeted therapies may synergize with immune cells, thus providing rationale for the development of combination therapies. Here, we review the current status of ongoing clinical trials investigating MAPK pathway inhibitors, such as BRAF and MAPK/ERK kinase (MEK) inhibitors, in combination with checkpoint inhibitors targeting programmed death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T cell associated antigen-4 (CTLA-4). A better understanding of an individual drug’s mechanism of action, patterns of acquired resistance, and the influence on immune cells will be critical for the development of novel combination therapies.

Original languageEnglish
Article number2531
JournalInternational journal of molecular sciences
Volume21
Issue number7
DOIs
Publication statusPublished - 2020 Apr 1

Keywords

  • BRAF inhibitor
  • Combination therapy
  • CTLA-4
  • Immune checkpoint inhibitor
  • MAPK targeted therapy
  • MEK inhibitor
  • PD-1
  • PD-L1

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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