Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors

Abstract

Human epidermal growth factor receptor 2 gene (HER2) is focally amplified in approximately 20% of breast cancers. HER2 inhibitors alone are not effective, and sensitizing agents will be necessary to move away from a reliance on heavily toxic chemotherapeutics. We recently demonstrated that the efficacy of HER2 inhibitors is mitigated by uniformly low levels of the myeloid cell leukemia 1 (MCL-1) endogenous inhibitor, NOXA. Emerging clinical data have demonstrated that clinically advanced cyclin-dependent kinase (CDK) inhibitors are effective MCL-1 inhibitors in patients, and, importantly, well tolerated. We, therefore, tested whether the CDK inhibitor, dinaciclib, could block MCL-1 in preclinical HER2-amplified breast cancer models and therefore sensitize these cancers to dual HER2/EGFR inhibitors neratinib and lapatinib, as well as to the novel selective HER2 inhibitor tucatinib. Indeed, we found dinaciclib suppresses MCL-1 RNA and is highly effective at sensitizing HER2 inhibitors both in vitro and in vivo. This combination was tolerable in vivo. Mechanistically, liberating the effector BCL-2 protein, BAK, from MCL-1 results in robust apoptosis. Thus, clinically advanced CDK inhibitors may effectively combine with HER2 inhibitors and present a chemotherapy-free therapeutic strategy in HER2-amplified breast cancer, which can be tested immediately in the clinic.

Knockdown of miR-15b partially reverses the cisplatin resistance of NSCLC through the GSK-3β/MCL-1 pathway

“…Overexpression of MCL-1 has been shown to be an important mechanism for the development of chemoresistance in cancer cells. 39,40 In this study, a significant reduction of GSK-3β expression and an increase in MCL-1 expression was observed in cisplatin-resistant NSCLC cells compared to standard NSCLC cells. Furthermore, we confirmed that the downregulation of GSK-3β and overexpression of MCL-1 was responsible for cisplatin resistance in NSCLC.…”

High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer

“…Floros et al explored inhibition of Bcl-2 in combination with lapatinib in HER2+ breast cancer cell lines. They did not detect a sensitizing effect of venetoclax to lapatinib in BT-474 or MDA-MB-453 cell lines [30]. In contrast to the KPL4 (and SUM190PT) cells, BT-474 is ER-positive, and MDA-MB-453 cells are PTEN wildtype [6].…”

MCL-1 is a clinically targetable vulnerability in breast cancer

“…Whilst most CDKs primarily function through mediating cell-cycle transition, CDK7/8/9 are critical for transcription by RNA polymerase II. Indeed, inhibition of CDKs with dinaciclib has demonstrated promising clinical efficacy in pre-clinical models of lymphoma and HER2 -amplified breast cancers [ 59 , 60 ]. This process is reliant upon inhibition of MCL1 transcription, liberation of pro-apoptotic BAK and subsequent BAK-induced mitochondrial apoptosis [ 59 , 60 ].…”

“…Indeed, inhibition of CDKs with dinaciclib has demonstrated promising clinical efficacy in pre-clinical models of lymphoma and HER2 -amplified breast cancers [ 59 , 60 ]. This process is reliant upon inhibition of MCL1 transcription, liberation of pro-apoptotic BAK and subsequent BAK-induced mitochondrial apoptosis [ 59 , 60 ]. Interestingly, targeted CDK9 inhibitors, such as voruciclib, potently induce apoptosis through MCL-1 depletion in many hematologic cell lines and in a subset of breast cancer cell lines, and have recently entered clinical trials for the treatment of hematological malignancies ( Figure 3 ) [ 61 , 62 ].…”