{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T03:48:18Z","timestamp":1788666498594,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T00:00:00Z","timestamp":1692748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"VCU Massey Cancer Center P01 Pilot","award":["NIH-NCI R21 CA259782"],"award-info":[{"award-number":["NIH-NCI R21 CA259782"]}]},{"name":"VCU Massey Cancer Center P01 Pilot","award":["R01 CA239706"],"award-info":[{"award-number":["R01 CA239706"]}]},{"name":"VCU Massey Cancer Center P01 Pilot","award":["P30 CA016059"],"award-info":[{"award-number":["P30 CA016059"]}]},{"name":"NIH-NCI Cancer Center","award":["NIH-NCI R21 CA259782"],"award-info":[{"award-number":["NIH-NCI R21 CA259782"]}]},{"name":"NIH-NCI Cancer Center","award":["R01 CA239706"],"award-info":[{"award-number":["R01 CA239706"]}]},{"name":"NIH-NCI Cancer Center","award":["P30 CA016059"],"award-info":[{"award-number":["P30 CA016059"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Through a unique genomics and drug screening platform with ~800 solid tumor cell lines, we have found a subset of SCLC cell lines are hypersensitive to venetoclax, an FDA-approved inhibitor of BCL-2. SCLC-A (ASCL1 positive) and SCLC-P (POU2F3 positive), which make up almost 80% of SCLC, frequently express high levels of BCL-2. We found that a subset of SCLC-A and SCLC-P showed high BCL-2 expression but were venetoclax-resistant. In addition, most of these SCLC cell lines have TP53 missense mutations, which make a single amino acid change. These mutants not only lose wild-type (WT) p53 tumor suppressor functions, but also acquire novel cancer-promoting activities (oncogenic, gain-of-function). A recent study with oncogenic mutant (Onc)-p53 knock-in mouse models of SCLC suggests gain-of-function activity can attenuate chemotherapeutic efficacy. Based on these observations, we hypothesize that Onc-p53 confers venetoclax resistance and that simultaneous inhibition of BCL-2 and Onc-p53 induces synergistic anticancer activity in a subset of SCLC-A and SCLC-P. We show here that (1) down-regulation of Onc-p53 increases the expression of a BH3-only pro-apoptotic BIM and sensitizes to venetoclax in SCLC-P cells; (2) targeting Onc-p53 by the HSP90 inhibitor, ganetespib, increases BIM expression and sensitizes to venetoclax in SCLC-P and SCLC-A cells. Although there are currently many combination studies for venetoclax proposed, the concept of simultaneous targeting of BCL-2 and Onc-p53 by the combination of venetoclax and HSP90 inhibitors would be a promising approach for SCLC treatment.<\/jats:p>","DOI":"10.3390\/ijms241713082","type":"journal-article","created":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T07:25:24Z","timestamp":1692775524000},"page":"13082","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment"],"prefix":"10.3390","volume":"24","author":[{"given":"Victoria","family":"Neely","sequence":"first","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alekhya","family":"Manchikalapudi","sequence":"additional","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khanh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista","family":"Dalton","sequence":"additional","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Koblinski","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony C.","family":"Faber","sequence":"additional","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumitra","family":"Deb","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, School of Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5993-1289","authenticated-orcid":false,"given":"Hisashi","family":"Harada","sequence":"additional","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s11912-010-0120-5","article-title":"Small cell lung cancer: Past, present, and future","volume":"12","author":"Rodriguez","year":"2010","journal-title":"Curr. 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