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

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-X L /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-X L and BCL-2 to be the most common expression profile. S63845 was effective in high MCL1-and low BCL-X L -expressing SCLC cell lines. S63845 induced BAKdependent apoptosis in vitro, and the anti-tumor efficacy was confirmed in an in vivo model. Although knockdown of BCL-X L and BCL-2 improved the cytotoxic activity of S63845 and its combination with navitoclax increased the antitumor cytotoxicity, the therapeutic range of S63845 with navitoclax was narrow in in vivo studies. Our study suggests MCL1 inhibition therapy be applied for high MCL1-and low BCL-X L -expressing SCLC patients.

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

“…Seven studied SCLC cell lines displayed differential addiction to either BCL-2, BCL-xL or MCL-1 for their survival, and the predominant protein expression of BCL-2, BCL-xL or MCL-1 could be used as a surrogate marker for this selective addiction [ 55 ]. High expression of MCL-1, associated with low expression of BCL-xL and BCL-2, was recently described in a small series of SCLC biopsies [ 56 ]. The MCL-1 inhibitor S63845 reduced viability of SCLC cell lines in vitro with an IC50 of 23 to 78 nM by inducing apoptosis, while in vivo treatment of two xenograft models reduced tumor volumes to a comparable degree as cisplatin in combination with etoposide [ 56 ].…”

“…High expression of MCL-1, associated with low expression of BCL-xL and BCL-2, was recently described in a small series of SCLC biopsies [ 56 ]. The MCL-1 inhibitor S63845 reduced viability of SCLC cell lines in vitro with an IC50 of 23 to 78 nM by inducing apoptosis, while in vivo treatment of two xenograft models reduced tumor volumes to a comparable degree as cisplatin in combination with etoposide [ 56 ]. SCLCs with high BCL-xL expression were less sensitive to S63845 and its knockdown sensitized cells to MCL-1 targeting.…”

“…SCLCs with high BCL-xL expression were less sensitive to S63845 and its knockdown sensitized cells to MCL-1 targeting. Accordingly, the combination of navitoclax (a dual inhibitor of BCL-xL and BCL-2) and S63845 reduced the cell viability of SCLC cell lines and showed in vivo synergistic effects in S63845-resistant xenograft model [ 56 ].…”

Novel gene signatures for stage classification of the squamous cell carcinoma of the lung

“…Some biological functions of some nodes in this network are well known to be relevant for cancer progression as PTEN which is a tumor suppressor altered in some types of cancer, as well as others like MCL1 which is an anti-apoptotic protein altered in some types of cancers. Also, MCL1 is being studied as a target for cancer patient treatment in small cell lung cancer 28 , 29 . FAR1 is observed to play an essential role in the production of ether lipids/plasmalogens whose synthesis requires fatty alcohol.…”

MicroRNAs Involved in Small-cell Lung Cancer as Possible Agents for Treatment and Identification of New Targets

“…Inhibition of MCL1 with small molecules has been pursued in several types of cancer, such as myeloma, follicular lymphoma and advanced SCLC in advanced clinical studies (100-102). MCL1 inhibition has been shown to be effective against a subset of SCLCs with high MCL1 and low B-cell lymphoma-extra large (BCL-XL) expression (101). miR-126.…”