mTOR Inhibition for Cancer Therapy: Past, Present and Future by Monica Mita Alain Mita & Eric K. Rowinsky

Author:Monica Mita, Alain Mita & Eric K. Rowinsky
Language: eng
Format: epub
Publisher: Springer Paris, Paris

7.5 Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) is characterized by unregulated growth of myeloid precursors in the bone marrow and proliferation of mature granulocytes (neutrophils, eosinophils, and basophils) in the peripheral blood. CML became a model for effective molecular targeted therapy when the discovery of the oncogenic fusion protein, BCR-ABL, produced by the t(9, 22) translocation, led to the development of tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, and nilotinib. Despite the success of these agents, resistance can develop due to the emergence of mutations in the BCR-ABL kinase domain, such as the T315I mutation caused by an amino acid substitution at position 315 in BCR- ABL1, from a threonine (T) to an isoleucine (I), hindering the binding of TKIs. Other BCR-ABL mutations that confer varying degrees of resistance to TKIs are also emerging making targeting of pathways downstream of BCR-ABL more attractive.

The mTOR/PI3K pathway is a major effector signaling pathway downstream from BCR-ABL that in turn triggers the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α), both of which result in increased angiogenesis in CML [45]. In one small pilot study, Sillaber et al. [46] treated six patients with imatinib-resistant CML in hematological relapse (leukocytes >20,000 μL−1) with rapamycin. Two patients had a major leukocyte response with a decrease in WCC to less than 10,000 μL−1 with minor transient responses seen in two other patients. Responding patients also had decrease in VEGF mRNA levels in circulating leukemic cells with in vivo inhibition of imatinib-resistant (including T315I mutated) cells of BCR-ABL. Another preclinical study reported that the dual mTORC1/2 inhibitor, OSI-0217, induced apoptosis in CML progenitors including T315I mutant cells [47]. PI3K inhibition is also being studied in combination with TKIs and has displayed favorable results in preclinical studies. In one study, LY294002, a potent PI3K inhibitor, was able to restore nilotinib-induced apoptosis of CML stem cells that were previously refractory to nilotinib due to activation of the SCF survival pathway [48]. NVP-BEZ235, a dual PI3K and mTORC 1/2 inhibitor, has also been shown to be effective in enhancing cytotoxicity in CML stem cells and progenitor with different TKIs [49]. CML stem cells are thought to be generally resistant to TKI making cure with TKI therapy alone unlikely. These studies suggest that combining TKIs with inhibitors of the mTOR/PI3K pathway may effectively target CML stem cells and offer the possibility of cure in addition to overcoming resistance.

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