Targeting Melanoma's MCL1 Bias Unleashes the Apoptotic Potential of BRAF and ERK1/2 Pathway Inhibitors

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Nov 16

PMID 31727888

Citations 39

Authors

Matthew J Sale

Emma Minihane

Noel R Monks

Rebecca Gilley

Frances M Richards

Kevin P Schifferli

Courtney L Andersen

Emma J Davies

Mario Aladren Vicente

Eiko Ozono

Aleksandra Markovets

Jonathan R Dry

Lisa Drew

Vikki Flemington

Theresa Proia

Duncan I Jodrell

Paul D Smith

Simon J Cook

Affiliations

Soon will be listed here.

Abstract

BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-X expression in melanoma biases the pro-survival pool towards MCL1. Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, driving profound tumour cell death that requires BAK/BAX, BIM and BMF, and inhibiting tumour growth in vivo. Combination of ERK1/2 pathway inhibitors with BCL2/BCL-w/BCL-X inhibitors is stronger in CRC, correlating with a low MCL1:BCL-X ratio; indeed the MCL1:BCL-X ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL2/BCL-w/BCL-X inhibitors. Finally, AZD5991 delays acquired BRAFi/MEKi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi + MEKi resistance. Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes.

Citing Articles

Potential biomarkers for MCL1 inhibitor sensitivity.

Duan L, Maki C Cell Signal (Middlet). 2025; 2(1):144-147.

PMID: 39802137 PMC: 11720113. DOI: 10.46439/signaling.2.046.

Small molecule Mcl-1 inhibitor for triple negative breast cancer therapy.

Dong S, Alahari S Front Cell Dev Biol. 2024; 12:1408107.

PMID: 39372954 PMC: 11449857. DOI: 10.3389/fcell.2024.1408107.

Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent Activities in Mouse Models of Hematological and Solid Tumors.

Tarr J, Salovich J, Aichinger M, Jeon K, Veerasamy N, Sensintaffar J J Med Chem. 2024; 67(16):14370-14393.

PMID: 39102508 PMC: 11345828. DOI: 10.1021/acs.jmedchem.4c01188.

Roles and mechanisms of aberrant alternative splicing in melanoma - implications for targeted therapy and immunotherapy resistance.

Chen W, Geng D, Chen J, Han X, Xie Q, Guo G Cancer Cell Int. 2024; 24(1):101.

PMID: 38462618 PMC: 10926661. DOI: 10.1186/s12935-024-03280-x.

MCL1 inhibition targets Myeloid Derived Suppressors Cells, promotes antitumor immunity and enhances the efficacy of immune checkpoint blockade.

Mukherjee N, Katsnelson E, Brunetti T, Michel K, Couts K, Lambert K Cell Death Dis. 2024; 15(3):198.

PMID: 38459020 PMC: 10923779. DOI: 10.1038/s41419-024-06524-w.

References

You H, Pellegrini M, Tsuchihara K, Yamamoto K, Hacker G, Erlacher M . FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal. J Exp Med. 2006; 203(7):1657-63. PMC: 2118330. DOI: 10.1084/jem.20060353. View

Flaherty K, Robert C, Hersey P, Nathan P, Garbe C, Milhem M . Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012; 367(2):107-14. DOI: 10.1056/NEJMoa1203421. View

Kawakami H, Huang S, Pal K, Dutta S, Mukhopadhyay D, Sinicrope F . Mutant BRAF Upregulates MCL-1 to Confer Apoptosis Resistance that Is Reversed by MCL-1 Antagonism and Cobimetinib in Colorectal Cancer. Mol Cancer Ther. 2016; 15(12):3015-3027. PMC: 5136313. DOI: 10.1158/1535-7163.MCT-16-0017. View

Dijkers P, Medema R, Lammers J, Koenderman L, Coffer P . Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol. 2000; 10(19):1201-4. DOI: 10.1016/s0960-9822(00)00728-4. View

Serasinghe M, Missert D, Asciolla J, Podgrabinska S, Wieder S, Izadmehr S . Anti-apoptotic BCL-2 proteins govern cellular outcome following B-RAF(V600E) inhibition and can be targeted to reduce resistance. Oncogene. 2014; 34(7):857-67. PMC: 4160434. DOI: 10.1038/onc.2014.21. View

Zhong Q, Gao W, Du F, Wang X . Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell. 2005; 121(7):1085-95. DOI: 10.1016/j.cell.2005.06.009. View

Sale M, Balmanno K, Saxena J, Ozono E, Wojdyla K, McIntyre R . MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAF amplification whereas KRAS amplification promotes EMT-chemoresistance. Nat Commun. 2019; 10(1):2030. PMC: 6497655. DOI: 10.1038/s41467-019-09438-w. View

Lopez J, Hesling C, Prudent J, Popgeorgiev N, Gadet R, Mikaelian I . Src tyrosine kinase inhibits apoptosis through the Erk1/2- dependent degradation of the death accelerator Bik. Cell Death Differ. 2012; 19(9):1459-69. PMC: 3422470. DOI: 10.1038/cdd.2012.21. View

Frederick D, Fragomeni R, Schalck A, Ferreiro-Neira I, Hoff T, Cooper Z . Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. PLoS One. 2014; 9(7):e101286. PMC: 4077767. DOI: 10.1371/journal.pone.0101286. View

10.

Ni Chonghaile T, Letai A . Mimicking the BH3 domain to kill cancer cells. Oncogene. 2009; 27 Suppl 1:S149-57. PMC: 3733265. DOI: 10.1038/onc.2009.52. View

11.

Smith A, Dai H, Correia C, Takahashi R, Lee S, Schmitz I . Noxa/Bcl-2 protein interactions contribute to bortezomib resistance in human lymphoid cells. J Biol Chem. 2011; 286(20):17682-92. PMC: 3093844. DOI: 10.1074/jbc.M110.189092. View

12.

McGill G, Horstmann M, Widlund H, Du J, Motyckova G, Nishimura E . Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell. 2002; 109(6):707-18. DOI: 10.1016/s0092-8674(02)00762-6. View

13.

Lai Z, Markovets A, Ahdesmaki M, Chapman B, Hofmann O, McEwen R . VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res. 2016; 44(11):e108. PMC: 4914105. DOI: 10.1093/nar/gkw227. View

14.

Ghandi M, Huang F, Jane-Valbuena J, Kryukov G, Lo C, McDonald 3rd E . Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature. 2019; 569(7757):503-508. PMC: 6697103. DOI: 10.1038/s41586-019-1186-3. View

15.

Chen L, Willis S, Wei A, Smith B, Fletcher J, Hinds M . Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 2005; 17(3):393-403. DOI: 10.1016/j.molcel.2004.12.030. View

16.

Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno A, Le Toumelin-Braizat G . The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016; 538(7626):477-482. DOI: 10.1038/nature19830. View

17.

Sale M, Cook S . The BH3 mimetic ABT-263 synergizes with the MEK1/2 inhibitor selumetinib/AZD6244 to promote BIM-dependent tumour cell death and inhibit acquired resistance. Biochem J. 2012; 450(2):285-94. DOI: 10.1042/BJ20121212. View

18.

Cragg M, Jansen E, Cook M, Harris C, Strasser A, Scott C . Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic. J Clin Invest. 2008; 118(11):3651-9. PMC: 2571034. DOI: 10.1172/JCI35437. View

19.

Sheridan C, Brumatti G, Elgendy M, Brunet M, Martin S . An ERK-dependent pathway to Noxa expression regulates apoptosis by platinum-based chemotherapeutic drugs. Oncogene. 2010; 29(49):6428-41. DOI: 10.1038/onc.2010.380. View

20.

Tao Z, Hasvold L, Wang L, Wang X, Petros A, Park C . Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity. ACS Med Chem Lett. 2014; 5(10):1088-93. PMC: 4190639. DOI: 10.1021/ml5001867. View