BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAF V600E colorectal cancer
Abstract Metastatic BRAF V600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAFV600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall surviv...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-03-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06478-z |
| _version_ | 1797273038025129984 |
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| author | Laura J. Jenkins Ian Y. Luk Fiona Chionh Tao Tan Kristen Needham Jamieson Ayton Camilla M. Reehorst Natalia Vukelic Oliver M. Sieber Dmitri Mouradov Peter Gibbs David S. Williams Niall C. Tebbutt Jayesh Desai Frédéric Hollande Amardeep S. Dhillon Erinna F. Lee Delphine Merino W. Douglas Fairlie John M. Mariadason |
| author_facet | Laura J. Jenkins Ian Y. Luk Fiona Chionh Tao Tan Kristen Needham Jamieson Ayton Camilla M. Reehorst Natalia Vukelic Oliver M. Sieber Dmitri Mouradov Peter Gibbs David S. Williams Niall C. Tebbutt Jayesh Desai Frédéric Hollande Amardeep S. Dhillon Erinna F. Lee Delphine Merino W. Douglas Fairlie John M. Mariadason |
| author_sort | Laura J. Jenkins |
| collection | DOAJ |
| description | Abstract Metastatic BRAF V600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAFV600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. We have found that a limitation of Enc+Cet treatment is the failure to efficiently induce apoptosis in BRAF V600E CRCs, despite inducing expression of the pro-apoptotic protein BIM and repressing expression of the pro-survival protein MCL-1. Here, we show that BRAF V600E CRCs express high basal levels of the pro-survival proteins MCL-1 and BCL-XL, and that combining encorafenib with a BCL-XL inhibitor significantly enhances apoptosis in BRAF V600E CRC cell lines. This effect was partially dependent on the induction of BIM, as BIM deletion markedly attenuated BRAF plus BCL-XL inhibitor-induced apoptosis. As thrombocytopenia is an established on-target toxicity of BCL-XL inhibition, we also examined the effect of combining encorafenib with the BCL-XL -targeting PROTAC DT2216, and the novel BCL-2/BCL-XL inhibitor dendrimer conjugate AZD0466. Combining encorafenib with DT2216 significantly increased apoptosis induction in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAF V600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-XL inhibition significantly enhances apoptosis in pre-clinical models of BRAF V600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients. |
| first_indexed | 2024-03-07T14:38:49Z |
| format | Article |
| id | doaj.art-6e4f88d9b616433e88bdbae69ee002cc |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-07T14:38:49Z |
| publishDate | 2024-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-6e4f88d9b616433e88bdbae69ee002cc2024-03-05T20:30:28ZengNature Publishing GroupCell Death and Disease2041-48892024-03-011531910.1038/s41419-024-06478-zBCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAF V600E colorectal cancerLaura J. Jenkins0Ian Y. Luk1Fiona Chionh2Tao Tan3Kristen Needham4Jamieson Ayton5Camilla M. Reehorst6Natalia Vukelic7Oliver M. Sieber8Dmitri Mouradov9Peter Gibbs10David S. Williams11Niall C. Tebbutt12Jayesh Desai13Frédéric Hollande14Amardeep S. Dhillon15Erinna F. Lee16Delphine Merino17W. Douglas Fairlie18John M. Mariadason19Olivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstitutePersonalised Oncology Division, The Walter and Eliza Hall Institute of Medical ResearchOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstitutePersonalised Oncology Division, The Walter and Eliza Hall Institute of Medical ResearchPersonalised Oncology Division, The Walter and Eliza Hall Institute of Medical ResearchPersonalised Oncology Division, The Walter and Eliza Hall Institute of Medical ResearchOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstitutePeter MacCallum Cancer CentreDepartment of Clinical Pathology, The University of MelbourneThe institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin UniversityOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteAbstract Metastatic BRAF V600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAFV600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. We have found that a limitation of Enc+Cet treatment is the failure to efficiently induce apoptosis in BRAF V600E CRCs, despite inducing expression of the pro-apoptotic protein BIM and repressing expression of the pro-survival protein MCL-1. Here, we show that BRAF V600E CRCs express high basal levels of the pro-survival proteins MCL-1 and BCL-XL, and that combining encorafenib with a BCL-XL inhibitor significantly enhances apoptosis in BRAF V600E CRC cell lines. This effect was partially dependent on the induction of BIM, as BIM deletion markedly attenuated BRAF plus BCL-XL inhibitor-induced apoptosis. As thrombocytopenia is an established on-target toxicity of BCL-XL inhibition, we also examined the effect of combining encorafenib with the BCL-XL -targeting PROTAC DT2216, and the novel BCL-2/BCL-XL inhibitor dendrimer conjugate AZD0466. Combining encorafenib with DT2216 significantly increased apoptosis induction in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAF V600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-XL inhibition significantly enhances apoptosis in pre-clinical models of BRAF V600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients.https://doi.org/10.1038/s41419-024-06478-z |
| spellingShingle | Laura J. Jenkins Ian Y. Luk Fiona Chionh Tao Tan Kristen Needham Jamieson Ayton Camilla M. Reehorst Natalia Vukelic Oliver M. Sieber Dmitri Mouradov Peter Gibbs David S. Williams Niall C. Tebbutt Jayesh Desai Frédéric Hollande Amardeep S. Dhillon Erinna F. Lee Delphine Merino W. Douglas Fairlie John M. Mariadason BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAF V600E colorectal cancer Cell Death and Disease |
| title | BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAF V600E colorectal cancer |
| title_full | BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAF V600E colorectal cancer |
| title_fullStr | BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAF V600E colorectal cancer |
| title_full_unstemmed | BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAF V600E colorectal cancer |
| title_short | BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAF V600E colorectal cancer |
| title_sort | bcl xl inhibitors enhance the apoptotic efficacy of braf inhibitors in braf v600e colorectal cancer |
| url | https://doi.org/10.1038/s41419-024-06478-z |
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