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

Jenkins, LJ; Luk, IY; Chionh, F; Tan, T; Needham, K; Ayton, J; Reehorst, CM; Vukelic, N; Sieber, OM; Mouradov, D; Gibbs, P; Williams, DS; Tebbutt, NC; Desai, J; Hollande, F; Dhillon, AS; Lee, EF; Merino, D; Fairlie, WD; Mariadason, JM

Author(s): Jenkins, LJ; Luk, IY; Chionh, F; Tan, T; Needham, K; Ayton, J; Reehorst, CM; Vukelic, N; Sieber, OM; Mouradov, D; Gibbs, P; Williams, DS; Tebbutt, NC; Desai, J; Hollande, F; Dhillon, AS; Lee, EF; Merino, D; Fairlie, WD; Mariadason, JM;
Details: Publication Year 2024-03-01,Volume 15,Issue #3,Page 183
Journal Title: Cell Death & Disease
Publication Type: Research article
Abstract: 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.
Publisher: Springer Nature
Keywords: Animals; Humans; Mice; *Antineoplastic Agents/pharmacology/therapeutic use; *bcl-X Protein/antagonists & inhibitors/metabolism; *Carbamates; *Colorectal Neoplasms/drug therapy/genetics; Myeloid Cell Leukemia Sequence 1 Protein/genetics/metabolism; *Protein Kinase Inhibitors/pharmacology/therapeutic use; Proto-Oncogene Proteins B-raf/antagonists & inhibitors/genetics; Sulfonamides/pharmacology/therapeutic use; *Apoptosis/drug effects
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1038/s41419-024-06478-z
Open Access at Publisher's Site: https://doi.org/10.1038/s41419-024-06478-z
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-04-04 02:32:02

Last Modified: 2024-04-04 03:11:41