MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib

Young AIJ1, Castillo L1, Law AMK1, Brummer T2,3, Lee EF4,5,6, Fairlie EF4,5,6, Timpson P1,7, Gallego-Ortega D1,7, Ormandy CJ1,7 and Oakes SR1,7

  1. Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
  2. Centre for Biological Systems Analysis (ZBSA) and Centre for Biological Signallling Studies, Albert-Ludwigs-University, Stefan-Meier-Strasse 17, 79104, Freiburg, Germany.
  3. Spemann Graduate School for Biology and Medicine and Faculty of Biology, Albert-Ludwigs-University, Stefan-Meier-Strasse 17, 79104, Freiburg, Germany.
  4. Olivia Newton-John Cancer Research Institute, 145 Studley Rd, Heidelberg, Victoria, 3084, Australia.
  5. School of Cancer Medicine and Department of Chemistry and Physics, La Trobe University, Melbourne, Victoria, 3086, Australia.
  6. The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, 3052, Australia.
  7. St. Vincent’s Clinical School, UNSW Medicine, Victoria Street, Darlinghurst, NSW, 2052, Australia.

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. 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. 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 the lung in mouse mammary intraductal xenografts. Kinomic profiling revealed that MCL-1 antagonism modulated Src family kinases and their targets, 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. These data provide the first evidence that MCL-1 drives breast cancer cell invasion and suggests that MCL-1 antagonists could be used alone or in combination with drugs targeting Src kinases such as dasatinib to suppress metastasis.