mTORC1 inhibition induces resistance to methotrexate and 6-mercaptopurine in Ph+ and Ph-like B-ALL

Thanh Trang T. Vo, J. Scott Lee, Duc Nguyen, Brandon Lui, William Pandori, Andrew Khaw, Sharmila Mallya, Mengrou Lu, Markus Müschen, Marina Konopleva, David A. Fruman

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Elevated activity of mTOR is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high-risk B-ALL subtypes. Therefore, we tested whether mTOR inhibition can augment the efficacy of current chemotherapy agents in Ph+ and Ph-like B-ALL models. Surprisingly, inhibiting mTOR complex 1 (mTORC1) protected B-ALL cells from killing by methotrexate and 6-mercaptopurine, two antime-tabolite drugs used in maintenance chemotherapy. The cyto-protective effects correlated with decreased cell-cycle progression and were recapitulated using cell-cycle inhibitors, palbociclib or aphidicolin. Dasatinib, a tyrosine kinase inhibitor currently used in Ph+ patients, inhibits ABL kinase upstream of mTOR. Dasatinib resistance is mainly caused by ABL kinase mutations, but is also observed in a subset of ABL unmutated cases. We identified dasatinib-resistant Phþ cell lines and patient samples in which dasatinib can effectively reduce ABL kinase activity and mTORC1 signaling without causing cell death. In these cases, dasatinib protected leukemia cells from killing by 6-mercaptopurine. Using xenograft models, we observed that mTOR inhibition or dasatinib increased the numbers of leukemia cells that emerge after cessation of chemotherapy treatment. These results demonstrate that inhibitors targeting mTOR or upstream signaling nodes should be used with caution when combined with chemotherapeutic agents that rely on cell-cycle progression to kill B-ALL cells.

Original languageEnglish (US)
Pages (from-to)1942-1953
Number of pages12
JournalMolecular cancer therapeutics
Volume16
Issue number9
DOIs
StatePublished - Sep 2017

Fingerprint

6-Mercaptopurine
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Methotrexate
B-Lymphocytes
Cell Cycle
Phosphotransferases
Drug Therapy
Leukemia
Maintenance Chemotherapy
Aphidicolin
Withholding Treatment
Standard of Care
Combination Drug Therapy
Heterografts
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Dasatinib
Cell Death
Cell Count
Clinical Trials

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Vo, T. T. T., Lee, J. S., Nguyen, D., Lui, B., Pandori, W., Khaw, A., ... Fruman, D. A. (2017). mTORC1 inhibition induces resistance to methotrexate and 6-mercaptopurine in Ph+ and Ph-like B-ALL. Molecular cancer therapeutics, 16(9), 1942-1953. https://doi.org/10.1158/1535-7163.MCT-17-0024
Vo, Thanh Trang T. ; Lee, J. Scott ; Nguyen, Duc ; Lui, Brandon ; Pandori, William ; Khaw, Andrew ; Mallya, Sharmila ; Lu, Mengrou ; Müschen, Markus ; Konopleva, Marina ; Fruman, David A. / mTORC1 inhibition induces resistance to methotrexate and 6-mercaptopurine in Ph+ and Ph-like B-ALL. In: Molecular cancer therapeutics. 2017 ; Vol. 16, No. 9. pp. 1942-1953.
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Vo, TTT, Lee, JS, Nguyen, D, Lui, B, Pandori, W, Khaw, A, Mallya, S, Lu, M, Müschen, M, Konopleva, M & Fruman, DA 2017, 'mTORC1 inhibition induces resistance to methotrexate and 6-mercaptopurine in Ph+ and Ph-like B-ALL', Molecular cancer therapeutics, vol. 16, no. 9, pp. 1942-1953. https://doi.org/10.1158/1535-7163.MCT-17-0024

mTORC1 inhibition induces resistance to methotrexate and 6-mercaptopurine in Ph+ and Ph-like B-ALL. / Vo, Thanh Trang T.; Lee, J. Scott; Nguyen, Duc; Lui, Brandon; Pandori, William; Khaw, Andrew; Mallya, Sharmila; Lu, Mengrou; Müschen, Markus; Konopleva, Marina; Fruman, David A.

In: Molecular cancer therapeutics, Vol. 16, No. 9, 09.2017, p. 1942-1953.

Research output: Contribution to journalArticle

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T1 - mTORC1 inhibition induces resistance to methotrexate and 6-mercaptopurine in Ph+ and Ph-like B-ALL

AU - Vo, Thanh Trang T.

AU - Lee, J. Scott

AU - Nguyen, Duc

AU - Lui, Brandon

AU - Pandori, William

AU - Khaw, Andrew

AU - Mallya, Sharmila

AU - Lu, Mengrou

AU - Müschen, Markus

AU - Konopleva, Marina

AU - Fruman, David A.

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