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Targeting the Ubiquitin–Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer
PURPOSE: Small cell lung cancer (SCLC) is an aggressive disease with an overall 5-year survival rate of less than 10%. Treatment for SCLC with cisplatin/etoposide chemotherapy (C/E) ± radiotherapy has changed modestly over several decades. The ubiquitin-proteasome system is an underexplored therapeu...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9365348/ https://www.ncbi.nlm.nih.gov/pubmed/35165102 http://dx.doi.org/10.1158/1078-0432.CCR-21-0344 |
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author | Majeed, Safa Aparnathi, Mansi K. Nixon, Kevin C.J. Venkatasubramanian, Vidhyasagar Rahman, Fariha Song, Lifang Weiss, Jessica Barayan, Ranya Sugumar, Vijithan Barghout, Samir H. Pearson, Joel D. Bremner, Rod Schimmer, Aaron D. Tsao, Ming S. Liu, Geoffrey Lok, Benjamin H. |
author_facet | Majeed, Safa Aparnathi, Mansi K. Nixon, Kevin C.J. Venkatasubramanian, Vidhyasagar Rahman, Fariha Song, Lifang Weiss, Jessica Barayan, Ranya Sugumar, Vijithan Barghout, Samir H. Pearson, Joel D. Bremner, Rod Schimmer, Aaron D. Tsao, Ming S. Liu, Geoffrey Lok, Benjamin H. |
author_sort | Majeed, Safa |
collection | PubMed |
description | PURPOSE: Small cell lung cancer (SCLC) is an aggressive disease with an overall 5-year survival rate of less than 10%. Treatment for SCLC with cisplatin/etoposide chemotherapy (C/E) ± radiotherapy has changed modestly over several decades. The ubiquitin-proteasome system is an underexplored therapeutic target for SCLC. We preclinically evaluated TAK-243, a first-in-class small molecule E1 inhibitor against UBA1. EXPERIMENTAL DESIGN: We assessed TAK-243 in 26 SCLC cell-lines as monotherapy and combined with C/E, the PARP-inhibitor, olaparib, and with radiation using cell viability assays. We interrogated TAK-243 response with gene expression to identify candidate biomarkers. We evaluated TAK-243 alone and in combination with olaparib or radiotherapy with SCLC patient-derived xenografts (PDX). RESULTS: Most SCLC cell lines were sensitive to TAK-243 monotherapy (EC(50) median 15.8 nmol/L; range 10.2 nmol/L–367.3 nmol/L). TAK-243 sensitivity was associated with gene-sets involving the cell cycle, DNA and chromatin organization, and DNA damage repair, while resistance associated with cellular respiration, translation, and neurodevelopment. These associations were also observed in SCLC PDXs. TAK-243 synergized with C/E and olaparib in vitro across sensitive and resistant SCLC cell lines. Considerable TAK-243–olaparib synergy was observed in an SCLC PDX resistant to both drugs individually. TAK-243 radiosensitization was also observed in an SCLC PDX. CONCLUSIONS: TAK-243 displays efficacy in SCLC preclinical models. Enrichment of gene sets is associated with TAK-243 sensitivity and resistance. TAK-243 exhibits synergy when combined with genotoxic therapies in cell lines and PDXs. TAK-243 is a potential therapeutic strategy to improve SCLC patient outcomes, both as a single agent and in combination with existing therapies. |
format | Online Article Text |
id | pubmed-9365348 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-93653482023-01-05 Targeting the Ubiquitin–Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer Majeed, Safa Aparnathi, Mansi K. Nixon, Kevin C.J. Venkatasubramanian, Vidhyasagar Rahman, Fariha Song, Lifang Weiss, Jessica Barayan, Ranya Sugumar, Vijithan Barghout, Samir H. Pearson, Joel D. Bremner, Rod Schimmer, Aaron D. Tsao, Ming S. Liu, Geoffrey Lok, Benjamin H. Clin Cancer Res Translational Cancer Mechanisms and Therapy PURPOSE: Small cell lung cancer (SCLC) is an aggressive disease with an overall 5-year survival rate of less than 10%. Treatment for SCLC with cisplatin/etoposide chemotherapy (C/E) ± radiotherapy has changed modestly over several decades. The ubiquitin-proteasome system is an underexplored therapeutic target for SCLC. We preclinically evaluated TAK-243, a first-in-class small molecule E1 inhibitor against UBA1. EXPERIMENTAL DESIGN: We assessed TAK-243 in 26 SCLC cell-lines as monotherapy and combined with C/E, the PARP-inhibitor, olaparib, and with radiation using cell viability assays. We interrogated TAK-243 response with gene expression to identify candidate biomarkers. We evaluated TAK-243 alone and in combination with olaparib or radiotherapy with SCLC patient-derived xenografts (PDX). RESULTS: Most SCLC cell lines were sensitive to TAK-243 monotherapy (EC(50) median 15.8 nmol/L; range 10.2 nmol/L–367.3 nmol/L). TAK-243 sensitivity was associated with gene-sets involving the cell cycle, DNA and chromatin organization, and DNA damage repair, while resistance associated with cellular respiration, translation, and neurodevelopment. These associations were also observed in SCLC PDXs. TAK-243 synergized with C/E and olaparib in vitro across sensitive and resistant SCLC cell lines. Considerable TAK-243–olaparib synergy was observed in an SCLC PDX resistant to both drugs individually. TAK-243 radiosensitization was also observed in an SCLC PDX. CONCLUSIONS: TAK-243 displays efficacy in SCLC preclinical models. Enrichment of gene sets is associated with TAK-243 sensitivity and resistance. TAK-243 exhibits synergy when combined with genotoxic therapies in cell lines and PDXs. TAK-243 is a potential therapeutic strategy to improve SCLC patient outcomes, both as a single agent and in combination with existing therapies. American Association for Cancer Research 2022-05-02 2022-02-11 /pmc/articles/PMC9365348/ /pubmed/35165102 http://dx.doi.org/10.1158/1078-0432.CCR-21-0344 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Translational Cancer Mechanisms and Therapy Majeed, Safa Aparnathi, Mansi K. Nixon, Kevin C.J. Venkatasubramanian, Vidhyasagar Rahman, Fariha Song, Lifang Weiss, Jessica Barayan, Ranya Sugumar, Vijithan Barghout, Samir H. Pearson, Joel D. Bremner, Rod Schimmer, Aaron D. Tsao, Ming S. Liu, Geoffrey Lok, Benjamin H. Targeting the Ubiquitin–Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer |
title | Targeting the Ubiquitin–Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer |
title_full | Targeting the Ubiquitin–Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer |
title_fullStr | Targeting the Ubiquitin–Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer |
title_full_unstemmed | Targeting the Ubiquitin–Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer |
title_short | Targeting the Ubiquitin–Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer |
title_sort | targeting the ubiquitin–proteasome system using the uba1 inhibitor tak-243 is a potential therapeutic strategy for small-cell lung cancer |
topic | Translational Cancer Mechanisms and Therapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9365348/ https://www.ncbi.nlm.nih.gov/pubmed/35165102 http://dx.doi.org/10.1158/1078-0432.CCR-21-0344 |
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