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Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment
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 e...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10487506/ https://www.ncbi.nlm.nih.gov/pubmed/37685889 http://dx.doi.org/10.3390/ijms241713082 |
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author | Neely, Victoria Manchikalapudi, Alekhya Nguyen, Khanh Dalton, Krista Hu, Bin Koblinski, Jennifer E. Faber, Anthony C. Deb, Sumitra Harada, Hisashi |
author_facet | Neely, Victoria Manchikalapudi, Alekhya Nguyen, Khanh Dalton, Krista Hu, Bin Koblinski, Jennifer E. Faber, Anthony C. Deb, Sumitra Harada, Hisashi |
author_sort | Neely, Victoria |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10487506 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-104875062023-09-09 Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment Neely, Victoria Manchikalapudi, Alekhya Nguyen, Khanh Dalton, Krista Hu, Bin Koblinski, Jennifer E. Faber, Anthony C. Deb, Sumitra Harada, Hisashi Int J Mol Sci Article 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. MDPI 2023-08-23 /pmc/articles/PMC10487506/ /pubmed/37685889 http://dx.doi.org/10.3390/ijms241713082 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Neely, Victoria Manchikalapudi, Alekhya Nguyen, Khanh Dalton, Krista Hu, Bin Koblinski, Jennifer E. Faber, Anthony C. Deb, Sumitra Harada, Hisashi Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment |
title | Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment |
title_full | Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment |
title_fullStr | Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment |
title_full_unstemmed | Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment |
title_short | Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment |
title_sort | targeting oncogenic mutant p53 and bcl-2 for small cell lung cancer treatment |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10487506/ https://www.ncbi.nlm.nih.gov/pubmed/37685889 http://dx.doi.org/10.3390/ijms241713082 |
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