Poster Presentation 29th Lorne Cancer Conference 2017

MCL-1 inhibition combined with standard chemotherapy could be a safe strategy for cancer therapy (#128)

Kerstin Brinkmann 1 , Marco Herold 1 , Andreas Strasser 1
  1. Walter & Eliza Hall Institute of Medical Research, Parkville, ACT, Australia

Inefficient activation of the mitochondrial apoptotic pathway has been considered to be responsible for the resistance of tumour cells to a broad range of anti-cancer treatments. Mitochondrial apoptosis is regulated by pro- and anti-apoptotic BCL-2 proteins and, depending on their expression status in diverse cancers, anti-apoptotic proteins represent promising therapeutic targets1. Strikingly the prototype drugs ABT-263/navitoclax2,3 (inhibits BCL-2, BCL-X and BCL-W) and ABT-199/venetoclax4 (selective BCL-2-inhibitor) have already shown great promise in Phase I/II clinical trials and ABT-199 has recently been FDA-approved for treatment of CLL with 17p deletion5.

MCL-1 is unique amongst the anti-apoptotic BCL-2 family proteins as it is important at the earliest stages of embryonic development (e3.5)6. Tissue-specific ablation of Mcl-1 in adult mice demonstrated that MCL-1 is essential for the survival of a range of tissues and cell types, such as hematopoietic stem/progenitor cells7, B- and T-cells8,9, neutrophils10, heart and muscle. Furthermore, MCL-1 plays an essential role in the development and sustained growth of a variety of cancers11,12. Remarkably, loss of one allele of Mcl-1 results in the death of most MYC-driven lymphomas, with only minor impact on non-malignant cells12. Accordingly, MCL-1-inhibitors may preferentially kill tumour cells, identifying MCL-1 as a promising therapeutic target.

A common strategy for cancer therapy is the combinatorial use of several drugs, targeting different cellular pathways. Thus, it is essential to understand whether the combined therapy of conventional drugs and MCL-1-inhibition will be tolerated and efficacious. Remarkably, a recent study conducted in our laboratory revealed that loss of one allele of Mcl-1 severely compromised hematopoietic recovery after myeloablative challenge (treatment with 5-fluorouracil or g-irradiation)13. These results suggested that a combination of MCL-1 inhibitors and DNA damaging drugs could trigger unacceptable side effects. In order to mimic the combination of MCL-1-inhibition with other chemotherapeutics, we treated Mcl-1+/- mice with a broad range of chemotherapeutics. In contrast to the previous experiments, the present study revealed that a wide range of chemotherapeutics had no significant effect on the general well-being or haematopoietic compartment of mice with reduced MCL-1. Importantly, these results indicate that MCL-1 inhibition represents a safe option, even when combined with selected chemotherapeutics.

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