2. Academic Validation
  3. Constitutive BAK/MCL1 complexes predict paclitaxel and S63845 sensitivity of ovarian cancer

Constitutive BAK/MCL1 complexes predict paclitaxel and S63845 sensitivity of ovarian cancer

  • Cell Death Dis. 2021 Aug 12;12(8):789. doi: 10.1038/s41419-021-04073-0.
Dongyan Liu 1 2 3,  Xiaonan Hou 4,  Wangyu Wu 5,  Valentina Zanfagnin 4,  Yunjian Li 1 6,  Cristina Correia 7 8,  Zhiyang Zhao 1 2 3,  Chenggang Zhao 1 2 3,  Zhirong Liu 1 3,  Tao Zhang 5,  Zhiyou Fang 1 3,  Hongzhi Wang 1 3,  Chao Xu 2,  Saravut J Weroha 4 7,  Scott H Kaufmann 9 10,  Haiming Dai 11 12
Affiliations

Affiliations

  • 1 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health & Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
  • 2 University of Science and Technology of China, Hefei, 230026, China.
  • 3 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China.
  • 4 Division of Medical Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
  • 5 Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
  • 6 School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
  • 7 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA.
  • 8 Division of Oncology Research, Mayo Clinic, Rochester, MN, 55905, USA.
  • 9 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA. Kaufmann.Scott@mayo.edu.
  • 10 Division of Oncology Research, Mayo Clinic, Rochester, MN, 55905, USA. Kaufmann.Scott@mayo.edu.
  • 11 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health & Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China. Daih@cmpt.ac.cn.
  • 12 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. Daih@cmpt.ac.cn.
PMID: 34385422 DOI: 10.1038/s41419-021-04073-0
Abstract

We previously found that preformed complexes of Bak with antiapoptotic BCL2 proteins predict BH3 mimetic sensitivities in lymphohematopoietic cells. These complexes have not previously been examined in solid tumors or in the context of conventional Anticancer drugs. Here we show the relative amount of Bak found in preformed complexes with MCL1 or BCLXL varies across ovarian Cancer cell lines and patient-derived xenografts (PDXs). Cells bearing Bak/MCL1 complexes were more sensitive to paclitaxel and the MCL1 antagonist S63845. Likewise, PDX models with Bak/MCL1 complexes were more likely to respond to paclitaxel. Mechanistically, Bim induced by low paclitaxel concentrations interacted preferentially with MCL1 and displaced MCL1-bound Bak. Further studies indicated that cells with preformed Bak/MCL1 complexes were sensitive to the paclitaxel/S63845 combination, while cells without Bak/MCL1 complexes were not. Our study suggested that the assessment of Bak/MCL1 complexes might be useful for predicting response to paclitaxel alone or in combination with BH3 mimetics.

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