{"doi":"10.3390/ijms23137353","title":"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":"<jats:p>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.</jats:p>","journal":"International Journal of Molecular Sciences","year":2022,"id":592041,"datarank":1.9182348589804479,"base_score":4.634728988229636,"endowment":4.634728988229636,"self_citation_contribution":0.6952093482344455,"citation_network_contribution":1.2230255107460024,"self_endowment_contribution":0.6952093482344455,"citer_contribution":1.2230255107460024,"corpus_percentile":null,"corpus_rank":null,"citation_count":102,"citer_count":99,"citers_with_citation_signal":67,"citers_with_endowment":67,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":298996,"name":"Ann Richmond","orcid":"0000-0002-9580-900X","position":1,"is_corresponding":false},{"id":332267,"name":"Chi Yan","orcid":"0000-0002-8658-7302","position":2,"is_corresponding":false},{"id":1514877,"name":"Zhizhu Zhang","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"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":"<jats:p>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.</jats:p>","is_dataset_classified":null,"base_score":4.634728988229636,"endowment":4.634728988229636,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35806358","pmcid":"PMC9266842","openalex_id":"https://openalex.org/W4283790062","authors":[],"funders":[{"funder_name":"Lloyd Foundation Melanoma Research Grant (CY)","grant_id":"NCI R01-CA116021 (AR)","title":null},{"funder_name":"Lloyd Foundation Melanoma Research Grant (CY)","grant_id":"NCI-R01-CA243326 (AR)","title":null},{"funder_name":"Lloyd Foundation Melanoma Research Grant (CY)","grant_id":"IK6BX005225 (AR)","title":null},{"funder_name":"Lloyd Foundation Melanoma Research Grant (CY)","grant_id":"101BX002301 (AR)","title":null},{"funder_name":"BLRD VA","grant_id":"IK6 BX005225","title":null},{"funder_name":"BLRD VA","grant_id":"I01 BX002301","title":null},{"funder_name":"VA","grant_id":"101BX002301","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA116021","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01-CA116021","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01-CA243326","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA243326","title":null},{"funder_name":"National Institutes of Health","grant_id":"5IK6BX005225-04","title":"BLR&D Merit Review Research Career Scientist (RCS) Award (IK6)"},{"funder_name":"National Institutes of Health","grant_id":"5R01CA116021-09","title":"Impact of IKKB and AurK Inhibitors on Host Immunity and Melanoma"},{"funder_name":"National Institutes of Health","grant_id":"5R01CA243326-05","title":"Optimizing Response to Immune Checkpoint Inhibitor Therapy for Breast Cancer: A Role for Inhibitors of the PI3K pathway"}],"total_grants":14,"fwci":6.2678,"citation_percentile":0.97891871,"influential_citations":0,"citation_trend":[{"year":2022,"count":3},{"year":2023,"count":28},{"year":2024,"count":24},{"year":2025,"count":25},{"year":2026,"count":22}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1422-0067/23/13/7353/pdf?version=1656667479","host_type":"journal"},{"url":"https://www.mdpi.com/1422-0067/23/13/7353/pdf?version=1656667479","host_type":"GOLD"},{"url":"https://www.mdpi.com/1422-0067/23/13/7353/pdf?version=1656667479","host_type":"publisher"},{"url":"https://www.mdpi.com/1422-0067/23/13/7353/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/ijms23137353","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35806358","host_type":"repository"},{"url":"https://doaj.org/article/28199b79c233455d91de6ac194bfffec","host_type":"repository"},{"url":"https://dx.doi.org/10.3390/ijms23137353","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9266842","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9266842","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9266842?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.3390/ijms23137353","host_type":""}],"fields_of_study":["Melanoma and MAPK Pathways","Cancer Immunotherapy and Biomarkers","Histone Deacetylase Inhibitors Research","Medicine","Biology","0301 basic medicine","0303 health sciences","03 medical and health sciences","Humans","Immune Checkpoint Inhibitors","Melanoma","Mitogen-Activated Protein Kinase Kinases","Phosphatidylinositol 3-Kinases","Protein Kinase Inhibitors","Proto-Oncogene Proteins c-akt","Signal Transduction","TOR Serine-Threonine Kinases","Triple Negative Breast Neoplasms"],"mesh_terms":["Immune Checkpoint Inhibitors","Humans","Melanoma","Signal Transduction","Phosphatidylinositol 3-Kinases","Mitogen-Activated Protein Kinase Kinases","Protein Kinase Inhibitors","Proto-Oncogene Proteins c-akt","TOR Serine-Threonine Kinases","Triple Negative Breast Neoplasms"],"keywords":["PI3K/AKT/mTOR pathway","MAPK/ERK pathway","Triple-negative breast cancer","Cancer research","Melanoma","Protein kinase B","Medicine","Immune checkpoint","MEK inhibitor","Cancer","Targeted therapy","Breast cancer","Immune system","Immunotherapy","Immunology","Biology","Signal transduction","Internal medicine","Cell biology","Pi3k/akt/mtor","Immune Checkpoint Blockade","Mapk/mek/erk","Mitogen-Activated Protein Kinase Kinases","TOR Serine-Threonine Kinases","Triple Negative Breast Neoplasms","Review","Phosphatidylinositol 3-Kinases","Humans","Immune Checkpoint Inhibitors","Protein Kinase Inhibitors","Proto-Oncogene Proteins c-akt"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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