Overexpression of MCL-1 provides OCI-Ly1 with resistance toVenetocalx

Authors

  • Xinchi Zhang

DOI:

https://doi.org/10.61173/6p9d7k08

Keywords:

MCL-1, Venetoclax, OCI-Ly1

Abstract

Overexpression of MCL-1 is an antiapoptotic member of the BCL-2 family and has been seen in various human tumors,
correlating with the patient’s poor prognosis. This study tested whether cancers overexpress MCL-1 to gain resistance to
venetoclax. The expression of MCL-1 protein was measured by Western blot. Cell viability after venetoclax and MCL-1
inhibitor AZD5991 was added was measured by MTT. FP-based binding assays measured Venetoclax’s binding affinity
for MCL-1. The result of the study would give insights into venetoclax resistance and the overexpression of MCL-1 in
NHL OCI-Ly1. Future studies should focus on new drugs that can circumvent this resistance if the hypothesis is correct.

References

[1] Cancer, <https://www.who.int/news-room/fact-sheets/detail/ cancer> (2022).

[2] Singh, R. et al. Non-Hodgkin’s lymphoma: A review. J Family Med Prim Care 9, 1834-1840, doi:10.4103/jfmpc. jfmpc_1037_19 (2020).

[3] Armitage, J. O., Gascoyne, R. D., Lunning, M. A. & Cavalli, F. Non-Hodgkin lymphoma. Lancet 390, 298-310, doi:10.1016/ S0140-6736(16)32407-2 (2017).

[4] Non-Hodgkin lymphoma, <https://www.nhs.uk/conditions/ non-hodgkin-lymphoma/symptoms/> (2022).

[5] Thomas, L. W., Lam, C. & Edwards, S. W. Mcl-1; the molecular regulation of protein function. FEBS Lett 584, 2981- 2989, doi:10.1016/j.febslet.2010.05.061 (2010).

[6] Apoptosis, <https://www.genome.gov/genetics-glossary/ apoptosis> (2022).

[7] Leverson, J. D. et al. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT- 263 (navitoclax). Cell Death Dis 6, e1590, doi:10.1038/ cddis.2014.561 (2015).

[8] Xiang, W., Yang, C. Y. & Bai, L. MCL-1 inhibition in cancer treatment. Onco Targets Ther 11, 7301-7314, doi:10.2147/OTT. S146228 (2018).

[9] Montero, J. & Letai, A. Why do BCL-2 inhibitors work and where should we use them in the clinic? Cell Death Differ 25, 56-64, doi:10.1038/cdd.2017.183 (2018).

[10] Xu, C. et al. The prognostic significance of MCL1 copy number gain in esophageal squamous cell carcinoma. Oncotarget 8, 87699-87709, doi:10.18632/oncotarget.21181 (2017).

[11] Tahir, S. K. et al. Potential mechanisms of resistance to venetoclax and strategies to circumvent it. BMC Cancer 17, 399, doi:10.1186/s12885-017-3383-5 (2017).

[12] Kotschy, A. et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 538, 477-482, doi:10.1038/nature19830 (2016).

[13] Anti-MCL1 antibody (ab28147), <https://www.abcam.com/ mcl1-antibody-ab28147.html>

[14] Abulwerdi, F. A. et al. 3-Substituted-N-(4- hydroxynaphthalen-1-yl)arylsulfonamides as a novel class of selective Mcl-1 inhibitors: structure-based design, synthesis, SAR, and biological evaluation. J Med Chem 57, 4111-4133, doi:10.1021/jm500010b (2014).

Downloads

Published

2023-06-01