Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 13, Pages -Publisher
MDPI
DOI: 10.3390/ijms23137353
Keywords
melanoma; triple-negative breast cancer; PI3K; AKT; mTOR; MAPK; MEK; ERK; immune checkpoint blockade
Funding
- Lloyd Foundation Melanoma Research Grant
- Department of Veterans Affairs SRCS Award [IK6BX005225]
- Department of Veterans Affairs MERIT Award [101BX002301]
- [NCI R01-CA116021]
- [NCI-R01-CA243326]
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Hyperactivation of PI3K/AKT/mTOR and MAPK/MEK/ERK signaling pathways is common in various cancers, and targeting these pathways may enhance the response to immune checkpoint inhibitors (ICIs) as a strategy to overcome resistance.
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.
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