Immunomodulatory Properties of PI3K/AKT/mTOR and MAPK/MEK/ERK Inhibition Augment Response to Immune Checkpoint Blockade in Melanoma and Triple-Negative Breast Cancer

Abstract

Hyperactivation of PI3K/AKT/mTOR and MAPK/MEK/ERK signaling pathways is commonly observed in many cancers, including triple-negative breast cancer (TNBC) and melanoma. Moreover, the compensatory upregulation of the MAPK/MEK/ERK pathway has been associated with therapeutic resistance to targeted inhibition of the PI3K/AKT/mTOR pathway, and vice versa. The immune-modulatory effects of both PI3K and MAPK inhibition suggest that inhibition of these pathways might enhance response to immune checkpoint inhibitors (ICIs). ICIs have become the standard-of-care for metastatic melanoma and are recently an option for TNBC when combined with chemotherapy, but alternative options are needed when resistance develops. In this review, we present the current mechanistic understandings, along with preclinical and clinical evidence, that outline the efficacy and safety profile of combinatorial or sequential treatments with PI3K inhibitors, MAPK inhibitors, and ICIs for treatment of malignant melanoma and metastatic TNBC. This approach may present a potential strategy to overcome resistance in patients who are a candidate for ICI therapy with tumors harboring either or both of these pathway-associated mutations.

Dermokine mutations contribute to epithelial-mesenchymal transition and advanced melanoma through ERK/MAPK pathways

“…This was accompanied by the upregulation of MMP and vimentin genes, which may promote metastasis, suggesting that DMKN could be a malignancy-associated gene. In many in ammatory skin disorders, DMKN is a promising epithelial development biomolecular tool for gene therapy by coordinating various signaling pathways like TP53, PI3K/Akt, and TGF-β pathways 15,35 15,37,38 . However, the detailed underlying mechanism of MAPK and ERK signaling in melanoma is still unclear.…”

Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy

“…For instance, PI3K inhibition led to a reduction of tumor PD-L1 expression in PTENmutant TNBC and colorectal cancer (CRC) [152]. More specifically, the PI3Kα-specific or pan-PI3K inhibitor did not show an anti-tumor response over ICI alone in TNBC models, while the PI3K/mTOR dual inhibitor gedatolisib associated with ICIs induced a substantial cancer growth inhibition and a greater activation and response of T-cells, natural killer (NK)-cell, and dendritic cells (DC) [153].…”

Targeting mTOR for Anti-Aging and Anti-Cancer Therapy

“…These data suggest that a combination of immune checkpoint inhibitors and mTOR inhibitors may be more effective. In fact, many pharmaceutical companies are conducting clinical trials of combinations of PI3K/mTOR inhibitors and immune checkpoint inhibitors [ 97 , 98 , 99 ]. mTOR is required for Th1 and Th2 effector T cell differentiation.…”