Poster Presentation 30th Lorne Cancer Conference 2018

MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib. (#234)

Adelaide Young 1 , Andrew Law 1 , Lesley Castillo 1 , Sabrina Chong 1 , Hayley D Cullen 1 , Martin Koehler 2 , Sebastian Herzog 3 , Tilman Brummer 2 , Erinna F Lee 4 , Walter D Fairlie 4 , Morghan C Lucas 1 , David Herrmann 1 , Amr Allan 1 , Paul Timpson 1 5 , D. Neil Watkins 1 5 , Ewan KA Millar 6 , Sandra A O'Toole 7 , David Gallego-Ortega 1 5 , Christopher J Ormandy 1 5 , Samantha R Oakes 1 5
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Centre for Biological Systems Analysis (ZBSA) and Institute for Molecular Medicine and Cell Research,, Albert-Ludwigs-University, Stefan-Meier-Strasse 17, Freiburg, Germany
  3. Spemann Graduate School for Biology and Medicine and Faculty of Biology, Albert-Ludwigs-University, Stefan-Meier-Strasse 17, Freiburg, Germany
  4. Cell Death & Survival Group, Olivia Newton-John Cancer Research Institute, Heidelberg. , Victoria, Australia.
  5. St. Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia
  6. Department of Anatomical Pathology, SEALS, St George Hospital, Kogarah, NSW, Australia
  7. Department of Tissue, Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

Background: Metastatic disease is largely resistant to therapy and accounts for almost all cancer deaths. Myeloid cell leukemia-1 (MCL-1) is an important regulator of cell survival and chemo-resistance in a wide range of malignancies, and thus its inhibition may prove to be therapeutically useful.

Methods: To examine whether targeting MCL-1 may provide an effective treatment for breast cancer, we constructed inducible models of BIMs2A expression (a specific MCL-1 inhibitor) in MDA-MB-468 (MDA-MB-468-2A) and MDA-MB-231 (MDA-MB-231-2A) cells.

Results: MCL-1 inhibition caused apoptosis of basal-like MDA-MB-468-2A cells grown as monolayers, and sensitized them to the BCL-2/BCL-XL inhibitor ABT-263, demonstrating that MCL-1 regulated cell survival. In MDA-MB-231-2A cells, grown in an organotypic model, induction of BIMs2A produced an almost complete suppression of invasion. Apoptosis was induced in such a small proportion of these cells that it could not account for the large decrease in invasion, suggesting that MCL-1 was operating via a previously undetected mechanism. MCL-1 antagonism also suppressed local invasion and distant metastasis to lung in mouse mammary intraductal xenografts. Kinomic profiling revealed that MCL-1 antagonism modulated Src family kinase substrates, which suggested that MCL-1 might act as an upstream modulator of invasion via this pathway. Inhibition of MCL-1 in combination with dasatinib suppressed invasion in 3D models of invasion and inhibited the establishment of tumors in vivo.