mTORC1 Inhibition Induces Resistance to Methotrexate and 6-Mercaptopurine in Ph+ and Ph-like B-ALL

Elevated activity of the mechanistic target of rapamycin (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 anti-metabolite drugs used in maintenance chemotherapy. The cytoprotective 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 Ph+ cell lines and patient samples where 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.

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