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

被引:40
作者
Zhang, Zhizhu [1 ,2 ]
Richmond, Ann [1 ,2 ]
Yan, Chi [1 ,2 ]
机构
[1] Tennessee Valley Healthcare Syst, Dept Vet Affairs, Nashville, TN 37212 USA
[2] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37240 USA
关键词
melanoma; triple-negative breast cancer; PI3K; AKT; mTOR; MAPK; MEK; ERK; immune checkpoint blockade; BRAF INHIBITION; DOUBLE-BLIND; KINASE; MEK; VEMURAFENIB; ACTIVATION; RESISTANCE; PLACEBO; PATHWAY; CELLS;
D O I
10.3390/ijms23137353
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页数:15
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