Editors' ChoiceCancer

Double trouble for CML

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Science Translational Medicine  05 Apr 2017:
Vol. 9, Issue 384, e2773
DOI: 10.1126/scitranslmed.aan2773

Abstract

Combining two BCR-ABL1 inhibitors with nonoverlapping mechanisms of action eradicates CML and prevents recurrence.

The development of the BCR-ABL1 fusion oncoprotein inhibitor imatinib (otherwise known as Gleevec) is one of the greatest successes of targeted therapy. The use of this agent led not only to durable remissions in otherwise fatal chronic myeloid leukemias (CML) but also to the fevered pursuit of other tyrosine kinase inhibitors for cancer therapy. Although imatinib, which targets the catalytic site of BCR-ABL1, is extremely effective, a subset of CML patients never achieve a complete hematological response or develop resistance because of mutations in BCR-ABL1. Second-generation inhibitors such as nilotinib can overcome many of the resistance-causing mutations, but some mutations, including T315I, remain intractable to selective inhibitors.

To address this clinical challenge, Wylie et al. developed a potent and selective allosteric ABL1 inhibitor that binds the myristoyl pocket of ABL1, instead of the catalytic site, and induces an inactive kinase conformation. In a scientific tour de force, the authors extensively characterized the inhibitor molecule, ABL001, and demonstrated its potent in vitro and in vivo efficacy. As would perhaps be expected, the mutations that can produce resistance to this new agent are completely nonoverlapping with those that produce resistance to catalytic site inhibitors, raising the possibility of using them in combination with curative intent. Although the use of ABL001 either before or after nilotinib in a mouse model of CML led to eventual relapse, the concurrent use of the two agents eradicated tumor cells, which continued to be absent long after dosing was stopped.

The demonstration of a high percentage of presumable cures when the two inhibitors of the same oncoprotein were combined is notable and underscores the need for combination therapies to overcome the likely presence of resistant subclones within most malignancies. The blueprint for effective combination therapies with nonoverlapping mechanisms of action and resistance demonstrated in this manuscript will hopefully support meaningful improvements in patient outcomes in Gleevec-resistant CML as well as other diseases.

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