MCL1 inhibition is effective against a subset of small-cell lung cancer with high MCL1 and low BCL-XL expression.

Cell Death & Disease
Yuto YasudaToyohiro Hirai

Abstract

There have been few advances in the treatment of small-cell lung cancer (SCLC) because of the lack of targets. MCL1, a member of the anti-apoptotic BCL-2 family, may be a treatment target in several cancers, including SCLC. However, whether the expression profile of the anti-apoptotic BCL-2 family affects MCL1 inhibition strategy is unknown. A tissue microarray (TMA) was created from consecutive patients who were diagnosed with SCLC and had previously undergone surgery at Kyoto University Hospital (Kyoto, Japan) between 2001 and 2017. We used S63845, a MCL1 inhibitor, to assess the cytotoxic capacity in SCLC cell lines including a patient-derived cell line in vitro and in vivo. The combination of S63845 with navitoclax, a double BCL-XL/BCL-2 inhibitor, was also employed to examine the comprehensive inhibition of the anti-apoptotic BCL-2 family. Immunohistochemistry of a TMA from patients with surgically resected SCLC demonstrated high MCL1 expression with low BCL-XL and BCL-2 to be the most common expression profile. S63845 was effective in high MCL1- and low BCL-XL-expressing SCLC cell lines. S63845 induced BAK-dependent apoptosis in vitro, and the anti-tumor efficacy was confirmed in an in vivo model. Although knockdown of BC...Continue Reading

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Citations

Dec 15, 2020·Journal of Hematology & Oncology·Arnold BolomskyJo Caers
Nov 18, 2020·Biochemistry. Biokhimii︠a︡·V V SenichkinG S Kopeina
Mar 3, 2021·Scientific Reports·Angel Juarez-FloresMarco V José
Jul 5, 2021·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Noor A HusseinAmit K Tiwari
Aug 3, 2021·International Journal of Biological Macromolecules·Pooja MittalIndrakant Kumar Singh

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Methods Mentioned

BETA
Assay
Co-IP
Immunoprecipitation
Transfection
xenograft

Software Mentioned

ARRIVE
GraphPad Prism
GraphPad
HALO

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