{"doi":"10.1126/scisignal.add5073","title":"Protein phosphatase 6 activates NF-κB to confer sensitivity to MAPK pathway inhibitors in <i>KRAS</i> - and <i>BRAF</i> -mutant cancer cells","abstract":"The Ras–mitogen-activated protein kinase (MAPK) pathway is a major target for cancer treatment. To better understand the genetic pathways that modulate cancer cell sensitivity to MAPK pathway inhibitors, we performed a CRISPR knockout screen with MAPK pathway inhibitors on a colorectal cancer (CRC) cell line carrying mutant KRAS. Genetic deletion of the catalytic subunit of protein phosphatase 6 (PP6), encoded by PPP6C , rendered KRAS - and BRAF -mutant CRC and BRAF -mutant melanoma cells more resistant to these inhibitors. In the absence of MAPK pathway inhibition, PPP6C deletion in CRC cells decreased cell proliferation in two-dimensional (2D) adherent cultures but accelerated the growth of tumor spheroids in 3D culture and tumor xenografts in vivo. PPP6C deletion enhanced the activation of nuclear factor κB (NF-κB) signaling in CRC and melanoma cells and circumvented the cell cycle arrest and decreased cyclin D1 abundance induced by MAPK pathway blockade in CRC cells. Inhibiting NF-κB activity by genetic and pharmacological means restored the sensitivity of PPP6C -deficient cells to MAPK pathway inhibition in CRC and melanoma cells in vitro and in CRC cells in vivo. Furthermore, a R264 point mutation in PPP6C conferred loss of function in CRC cells, phenocopying the enhanced NF-κB activation and resistance to MAPK pathway inhibition observed for PPP6C deletion. These findings demonstrate that PP6 constrains the growth of KRAS - and BRAF -mutant cancer cells, implicates the PP6–NF-κB axis as a modulator of MAPK pathway output, and presents a rationale for cotargeting the NF-κB pathway in PPP6C -mutant cancer cells.","journal":"Science Signaling","year":2024,"id":448637,"datarank":0.3009135219361913,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.03214960155198305,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.03214960155198305,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":5,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9618,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1222323,"name":"Abigail Read","orcid":null,"position":1,"is_corresponding":false},{"id":623636,"name":"Christophe Cataisson","orcid":"0000-0003-2600-1573","position":2,"is_corresponding":false},{"id":271844,"name":"Howard H. Yang","orcid":"0000-0002-9291-631X","position":3,"is_corresponding":false},{"id":1267577,"name":"Wei‐Chun Lee","orcid":"0009-0009-9398-4208","position":4,"is_corresponding":false},{"id":339931,"name":"Benjamin E. Turk","orcid":"0000-0001-9275-4069","position":5,"is_corresponding":false},{"id":623637,"name":"Stuart H. Yuspa","orcid":"0000-0003-4785-337X","position":6,"is_corresponding":false},{"id":618143,"name":"Ji Luo","orcid":"0000-0001-5063-1626","position":7,"is_corresponding":false},{"id":690863,"name":"Haibo Zhang","orcid":"0000-0002-7057-8479","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:02:12.215092Z","pmid":"38743809","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}