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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.
Highlights
In recent years, the focus of cancer therapeutics has shifted from the treatment of cancers based on type and histology to those targeting specific gene mutation and its dysregulation
NCT03299088 is a phase Ib study investigating the safety of pembrolizumab and trametinib (MEK inhibitor) for the treatment of patients with metastatic KRAS-mutated non-small-cell lung cancer (NSCLC) [38]
NCT04061980 is a phase II clinical trial combining a Mitogen-activated protein kinase (MAPK) inhibitor and a PD-1 inhibitor [38]; this study aims to assess the efficacy and safety of encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor) with or without nivolumab in patients with BRAF V600-mutated metastatic and refractory thyroid cancer not responsive to radioiodine treatment (Table 10) [38]
Summary
The focus of cancer therapeutics has shifted from the treatment of cancers based on type and histology to those targeting specific gene mutation and its dysregulation. We review the current status of therapies targeting the MAPK pathway and immunotherapies, mainly focusing on melanoma and NSCLC, as well as other solid cancers, such as pancreatic cancer, CRC, and thyroid cancer (clinicaltrials.gov) Major drivers of these cancers include BRAF (V600E, V599E) and/or KRAS (G12C, G12D) along the MAPK pathways while immunotherapies were considered as a monotherapy or in combination in those tumors expressing PD-1 ligands. Initial in vitro and in vivo studies using BRAF-targeted therapies demonstrated increased melanoma antigen expression with tumor-infiltrating CD8+ T cells, and decreased levels of VEGF and immunosuppressive cytokines. PD-1 and Tim-3 expression were found to be increased in T cells and in their corresponding ligands in tumors [20] These phenotypes support the rationale for combination therapy with a MAPK-targeted inhibitor and immune checkpoint blockade (anti-PD-1, anti-PDL-1, or Tim-3)
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