<br>BCL-XL 抑制剂增强 BRAF 抑制剂在 BRAFV600E 结直肠癌中的凋亡功效,Cell Death & Disease

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BCL-XL 抑制剂增强 BRAF 抑制剂在 BRAFV600E 结直肠癌中的凋亡功效
Cell Death & Disease ( IF 8.1 ) Pub Date : 2024-03-01 , DOI: 10.1038/s41419-024-06478-z
Laura J Jenkins _{1,

2} , Ian Y Luk _{1,

2} , Fiona Chionh _{1,

2} , Tao Tan _{3,

4} , Kristen Needham _{1,

2} , Jamieson Ayton _{1,

2} , Camilla M Reehorst _{1,

2} , Natalia Vukelic _{1,

2} , Oliver M Sieber _{3,

4,

5,

6} , Dmitri Mouradov _{3,

4} , Peter Gibbs ₃ , David S Williams _{1,

2,

7} , Niall C Tebbutt _{1,

5,

8} , Jayesh Desai ₉ , Frédéric Hollande _{10,

11} , Amardeep S Dhillon ₁₂ , Erinna F Lee _{1,

2,

13} , Delphine Merino _{1,

2,

4,

14} , W Douglas Fairlie _{1,

2,

13} , John M Mariadason _{1,

2}

Affiliation

Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia.
School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia.
Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
Department of Surgery, The University of Melbourne, Melbourne, VIC, Australia.
Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia.
Department of Pathology, Austin Health, Melbourne, VIC, Australia.
Department of Medical Oncology, Austin Health, Melbourne, Australia.
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia.
The institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia.
Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.

转移性 BRAF^V600E 结直肠癌（CRC）预后极差，迫切需要有效的新疗法。虽然 BRAF^V600E 抑制剂 encorafenib 联合 EGFR 抑制剂西妥昔单抗（Enc+Cet）最近被批准用于该适应证，但总生存期仅增加了 3.6 个月，并且仅在 20% 的患者中观察到客观反应。我们发现 Enc+Cet 治疗的局限性是尽管诱导促凋亡蛋白 BIM 的表达并抑制促存活蛋白 MCL-1 的表达，但未能有效地诱导 BRAF^V600E CRC 中的细胞凋亡。在这里，我们表明 BRAF^V600E CRCs 表达高基础水平的促存活蛋白 MCL-1 和 BCL-X_L，并且将 encorafenib 与 BCL-X_L 抑制剂联合使用显着增强 BRAF^V600E CRC 细胞系的细胞凋亡。这种效应部分依赖于 BIM 的诱导，因为 BIM 缺失显着减弱了 BRAF 加 BCL-X_L 抑制剂诱导的细胞凋亡。由于血小板减少症是 BCL-X_L 抑制的既定靶向毒性，我们还检查了 encorafenib 与 BCL-X_L 靶向 PROTAC DT2216 和新型 BCL-2/BCL-X_L 抑制剂树状大分子偶联物AZD0466联合使用的效果。encorafenib 与 DT2216 联合使用显着增加了体外细胞凋亡诱导，而 encorafenib 与 AZD0466 联合使用在小鼠中具有良好的耐受性，与单独使用任何一种药物相比，进一步减少了 BRAF^V600E CRC 异种移植物的生长。总的来说，这些发现表明，BRAF 和 BCL-X_L 联合抑制在 BRAF^V600E CRC 临床前模型中显着增强了细胞凋亡，是一种值得临床研究以改善这些患者预后的联合方案。

"点击查看英文标题和摘要"

BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV600E colorectal cancer

Metastatic BRAF^V600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAF^V600E 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-X_L, and that combining encorafenib with a BCL-X_L 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-X_L inhibitor-induced apoptosis. As thrombocytopenia is an established on-target toxicity of BCL-X_L inhibition, we also examined the effect of combining encorafenib with the BCL-X_L -targeting PROTAC DT2216, and the novel BCL-2/BCL-X_L 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-X_L 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.

更新日期：2024-03-03

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