{"doi":"10.1002/ijc.35112","title":"Passengers, drivers, and “goners”","abstract":"Genetic alterations that confer resistance to molecularly targeted therapies are a distinct type of cancer-associated mutation.These mutations typically arise as passengers that have no discernable effect on cell growth and which are present in only a subpopulation of tumor cells.However, under the strong selective pressure of a specific and potent drug, these erstwhile passengers confer a new survival advantage and thus become drivers of post-treatment tumor evolution.A recent observation by Smith and Zain 1 hints at the complex phenotypes of therapeutic resistance, and may provide clues as to how resistance can be overcome.Targeted therapies have revolutionized the management of many types of cancer.Unfortunately, the effects of such drugs are frequently short-lived, as therapy-resistant cell clones expand and ultimately lead to disease recurrence.The treatment of chronic lymphocytic leukemia (CLL) and several other B cell malignancies with small molecule inhibitors of the Bruton's tyrosine kinase (BTK) is a case in point [2][3][4] .BTK and its substrate, phospholipase C2 (PLCG2), form a downstream pathway that is activated by B cell receptor signaling (Fig 1A).While BTK is not frequently mutated in CLL, its expression is typically upregulated and the pathway constitutively active.In the past decade, FDA-approved drugs that potently and irreversibly inhibit BTK, including ibrutinib (2013), acalabrutinib (2017), and zanubrutinib (2020), have greatly improved the outlook for CLL patients.Cases of relapse after treatment with BTK inhibitors (BTKi) are most frequently caused by one of several characteristic mutations in BTK itself (Fig 1B).In the encoded protein, these mutations directly interfere with inhibitor binding.Less frequently, drug resistance is caused by a variety of somatic mutations in PLCG2 that commonly cause constitutive, BTK-independent activation of the encoded PLCG2 signaling protein.Here's where the story gets interesting.Gain-of-function PLCG2 mutations are associated with two very different diseases.While somatic mutations in PLCG2 drive the recurrence of CLL, germline mutations in PLCG2 underlie a rare syndrome called autoinflammation-","journal":"International Journal of Cancer","year":2024,"id":475958,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.944,"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":74314,"name":"Fred Bunz","orcid":"0000-0003-0878-1553","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T02:06:25.428435Z","pmid":"39056587","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":[]}