Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers

by Selleckchem | Aug 24 2023

Cancers often overexpress anti-apoptotic Bcl-2 proteins for cell death evasion, a recognized hallmark of cancer progression. While estrogen receptor (ER)-α+ breast cancers express high levels of three anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1), pharmacological inhibition of Bcl-2 and/or Bcl-xL fails to induce cell death in ERα+ breast cancer cell lines, due to rapid and robust Mcl-1 upregulation. The mechanisms of acute Mcl-1 upregulation in response to Bcl-2/Bcl-xL inhibition remain undefined in in ERα+ breast cancers. We report here that blockade of Bcl-2 or Bcl-xL, alone or together, rapidly induced mTOR signaling in ERα+ breast cancer cells, rapidly increasing cap-dependent Mcl-1 translation. Cells treated with a pharmacological inhibitor of cap-dependent translation, or with the mTORC1 inhibitor RAD001/everolimus, displayed reduced protein levels of Mcl-1 under basal conditions, and failed to upregulate Mcl-1 protein expression following treatment with ABT-263, a pharmacological inhibitor of Bcl-2 and Bcl-xL. Although treatment with ABT-263 alone did not sustain apoptosis in tumor cells in culture or in vivo, ABT-263 plus RAD001 increased apoptosis to a greater extent than either agent used alone. Similarly, combined use of the selective Mcl-1 inhibitor VU661013 with ABT-263 resulted in tumor cell apoptosis and diminished tumor growth in vivo. These findings suggest that rapid Mcl-1 translation drives ABT-263 resistance, but can be combated directly using emerging Mcl-1 inhibitors, or indirectly through existing and approved mTOR inhibitors.

Comments:

The passage you provided describes a research study investigating the mechanisms behind the resistance of estrogen receptor (ER)-α+ breast cancer cells to pharmacological inhibition of the anti-apoptotic Bcl-2 proteins, Bcl-2 and Bcl-xL. In these ERα+ breast cancer cells, the rapid upregulation of another anti-apoptotic protein called Mcl-1 prevents cell death even when Bcl-2 and Bcl-xL are inhibited.

The researchers discovered that blocking Bcl-2 or Bcl-xL, either individually or together, led to the activation of mTOR signaling in ERα+ breast cancer cells. This activation of mTOR signaling resulted in increased translation (production) of Mcl-1 protein, specifically through a mechanism known as cap-dependent translation.

To confirm the role of cap-dependent translation in Mcl-1 upregulation and its impact on resistance to Bcl-2 and Bcl-xL inhibitors, the researchers used a pharmacological inhibitor of cap-dependent translation and an mTORC1 inhibitor called RAD001 (everolimus). Treating the cells with these inhibitors reduced the levels of Mcl-1 protein and prevented its upregulation upon treatment with ABT-263, a pharmacological inhibitor of Bcl-2 and Bcl-xL.

While treatment with ABT-263 alone did not induce sustained apoptosis (cell death) in the ERα+ breast cancer cells, the combination of ABT-263 and RAD001 increased apoptosis to a greater extent than either agent used alone. Additionally, when the selective Mcl-1 inhibitor VU661013 was combined with ABT-263, it resulted in tumor cell apoptosis and reduced tumor growth in vivo.

These findings suggest that the rapid upregulation of Mcl-1 protein is responsible for the resistance of ERα+ breast cancer cells to Bcl-2 and Bcl-xL inhibitors. However, this resistance can be overcome either directly by using emerging Mcl-1 inhibitors or indirectly through the use of existing mTOR inhibitors that are already approved for clinical use.