Abstract
Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.
Highlights
Breast cancer is the most common type of cancer in women and one of the top causes of mortality worldwide [1,2]
As one-third of estrogen receptor (ER)+ breast cancer patients relapse following current therapies and present a high risk of metastasis [17], we sought to identify new strategies to better treat this type of cancer
We used ipatasertib (AKT inhibitor) [41], which has already been tested for triple-negative breast cancer [42]; everolimus, alpelisib (PI3K inhibitor) [43,44], palbociclib (CDK4/6 inhibitor) [45], fulvestrant [46,47], that have been approved for hormone receptor positive breast cancer treatment, and the BH3 mimetics S63845 (MCL-1 inhibitor) [33] and ABT-199 (BCL-2 inhibitor) [35], which are currently being explored in clinical trials
Summary
Breast cancer is the most common type of cancer in women and one of the top causes of mortality worldwide [1,2]. Generating specific drugs against this receptor has been an extensive field of study to treat ER+ tumors for decades In this regard, one of the first developed anti-estrogens was tamoxifen, which blocks ER activity [15], achieving outstanding clinical results and overall improving breast cancer patient survival [14]. When a cancer cell is effectively treated, early changes in the BCL-2 family of proteins can be detected that precede apoptotic process engagement [24,25] In this regard, functional assay dynamic BH3 profiling (DBP) can measure these initial pre-apoptotic events and predict later cytotoxicity. By timely identification of this compensation, we can sequentially block these anti-apoptotic proteins with BH3 mimetics to overcome tumor adaptation to treatment, reaching high cytotoxicity in ER+ cancer cells where other standard therapies fail
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