Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade

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.

<p>Combination of Immune Checkpoint Inhibitors with Chemotherapy in Lung Cancer</p>

“…ICIs resistance is divided into primary or adaptive resistance and acquired resistance. 79 The mechanisms of primary or adaptive resistance including (a) Alteration of signaling pathways: MAPK, PI3K, WNT/β-catenin, and IFN, which suppressed the process of tumor antigen expression, tumor antigen presentation, and T cell infiltration; [80][81][82][83] (b) Lack of antigenic mutations; 84 (c) loss of tumor antigen expression; (d) loss of HLA expression; 85 (e) up-regulation of constitutive PD-L1 expression. 86 The mechanisms of acquired resistance including (a) loss of target antigen; 87 (b) loss of T cell function; 87 (c) inhibitory immune checkpoints in T cells (eg, VISTA, LAG-3, TIM-3); 88,89 (d) T cell exhaustion; 90 (e) immunosuppressive cells (eg, TAMs, Tregs and MDSCs); 91,92 (d) intestinal dysbacteriosis; 93 (f) release of cytokines and metabolites in tumor microenvironment (eg, TGF-β, CSF-1, and adenylate).…”

Advanced Merkel cell carcinoma—A focus on medical drug therapy

“…35 One practicable way to overcome acquired drug-resistance, which is remarkably high in patients treated with ipilimumab monotherapy, is the combination of different drug and the combination with radiotherapy. 36 INCMGA00012 is a humanized IG4k monoclonal antibody against human PD-1, that has shown activity in solid tumors with an acceptable safety profile, is currently under investigation for metastatic MCC in a phase II trial (ClinicalTrials.gov Identifier: NCT03599713). [38][39][40] T A B L E 1 Recent trials on drug therapy of advanced or metastatic MCC…”

Molecular Insights on Potential Combination of Mapk Inhibitors Together with HCQ and HCQs Analogs in Viral Infection

“…Moreover, MAPK may also control inflammatory cytokine production and cellular apoptosis upon viral infection, integrating signals from complex intracellular networks in performing cellular functions, thus being a rather obvious target to fight against viral infection. Due to the initial discovery of the core elements of the MAPK pathways nearly four decades ago, considerable effort has been focused on development of MAPK inhibitors which have shown promising clinical responses in cancer patients, both as single inhibitors or in combination [7]. The pandemic crisis imposes to think about high-throughput molecular approaches to moving from operational to scientifically-driven pharmacovigilance.…”

“…Members of the Ras family of proteins, including K-Ras, H-Ras, and N-Ras, play a key role in transmission of extracellular signals into thecells [4]. Since decades, intense work is under way to develop and evaluate compounds that target components of MAPK pathways, for the treatment of inflammatory and neurodegenerative diseases, and of cancer [5], [6], [7]. CQ (N4-(7-Chloro-4-quinolinyl)-N1,N1-diethyl-1,4-pentanediamine) has long been used to treat malaria and amebiasis.…”