Involvement of MCL1, c-myc, and cyclin D2 protein degradation in ponatinib-induced cytotoxicity against T315I(+) Ph+leukemia cells

  • Biochem Biophys Res Commun. 2020 May 14;525(4):1074-1080. doi: 10.1016/j.bbrc.2020.02.165.
Chisato Inoue  1 ,  Sayaka Sobue  1 ,  Yoshiyuki Kawamoto  1 ,  Yuji Nishizawa  1 ,  Masatoshi Ichihara  1 ,  Akihiro Abe  2 ,  Fumihiko Hayakawa  3 ,  Motoshi Suzuki  4 ,  Yoshinori Nozawa  5 ,  Takahsi Murate  6
Affiliations
  • 1. College of Life and Health Sciences, Chubu University, Kasugai, 487-8501, Japan.
  • 2. Department of Hematology and Oncology, Fujita Health University, Toyoake, 470-1192, Japan.
  • 3. Department of Medical Technology, Nagoya University Graduate School of Health Sciences, Nagoya, 461-8673, Japan.
  • 4. Department of Molecular Oncology, Fujita Health University, Toyoake, 470-1192, Japan.
  • 5. Tokai Gakuin University, Kakamigahara, 504-8511, Japan.
  • 6. College of Life and Health Sciences, Chubu University, Kasugai, 487-8501, Japan. Electronic address: [email protected].
PMID: 32184020 DOI: 10.1016/j.bbrc.2020.02.165
Abstract

T315I mutation found in chronic myelogenous leukemia (CML) and Ph + ALL patients is the most serious one among resistance against BCR/ABL kinase inhibitors including imatinib and is only responsive to ponatinib (PNT). However, the novel strategy is required to reduce life-threatening adverse effects of PNT including ischemic Cardiovascular Disease. We examined the mechanism of PNT-induced cytotoxicity against a T315I(+) Ph + ALL cell line, TccY/Sr. PNT induced Apoptosis (increased sub G1 cells, and cleaved caspase3 and PARP), and suppressed protein expression of MCL1, cyclin D2 and c-Myc, which were reversed by a Proteasome Inhibitor, MG132, suggesting enhanced proteasomal degradation by PNT. Among BCL2 family inhibitors, MCL1 inhibitors (maritoclax and AZD5991) robustly induced cell death, showing the MCL1-dependent survival of TccY/Sr cells. Decreased MCL1 and c-Myc expression by PNT was also observed in T315I(+) MEGA2/STIR cells. PNT suppressed PI3K activation followed by Akt inhibition and GSK3 dephosphorylation. PI3K/Akt inhibitors mimicked PNT, suggesting that PI3K/Akt signaling is important for survival of TccY/Sr cells. Moreover, GSK3 inhibitor (SB216763) reduced PNT-induced cytotoxicity and degradation of c-Myc and MCL1. AZD5991 exhibited the synergistic action with PNT, anti-cancer drugs and venetoclax (BCL2 inhibitor), suggesting the utility of MCL1 inhibitor alone or in combination as a future clinical option for Ph + leukemia patients.

Keywords
MCL1; MCL1 inhibitors; Ponatinib; Protein degradation; T315I-positive Ph+ leukemia cell; c-myc.
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