BCR-ABL1 Inhibitor Axitinib Overcomes Drug Resistance in CML

While selective BCR-ABL tyrosine kinase inhibitors (TKIs) have markedly improved outcomes for patients with chronic myeloid leukemia (CML), they are not as effective in patient who carry the BCR-ABL1 (T315I) mutation, whose disease is often resistant to treatment. According to results reported in a research letter published in Nature, though, patients may have a new therapy option with axitinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor previously approved for second-line treatment of advanced renal cell carcinoma.

Tea Pemovska, MD, and colleagues, reported that axitinib inhibited the BCR-ABL (T315I) mutation in samples from patients with CML and Philadelphia chromosome–positive B-cell acute lymphocytic leukemia (Ph+ ALL). According to the authors, this was an “unexpected” finding, and one that brings hope to patients with drug-resistant CML and Ph+ B-cell ALL.

“Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukemia patients,” the authors wrote. The only other approved treatment option for these patients is the ABL1 inhibitor ponatinib, which has toxicity limitations.

To determine axitinib’s efficacy in this population, Dr. Pemovska, from the University of Helsinki in Finland, and her team examined cancer cells ex vivo from patients with T315I CML and B-ALL who had developed resistance to currently available treatments.

Using phenotypic drug sensitivity and resistance testing, they determined the growth response of the cells to a panel of 252 drugs (125 already approved and 127 investigative). As they expected, the growth of T315I cancer cells was inhibited by ponatinib and drugs that targeted molecules downstream of BCR-ABL signaling, but not by imatinib, nilotinib, or dasatinib, the most commonly used TKIs for patients with CML or Ph+ ALL.

The authors pointed out that the kinase activity of the T315I mutation was inhibited at a very low concentration of axitinib (100 nM), which compared favorably with the concentration required to inhibit the tyrosine kinase activity of VEGFR (20 nM). The activity of wild-type BCR-ABL kinase was inhibited with a significantly higher concentration of axitinib (3800 nM) – suggesting that axitinib specifically and potently inhibits BCR-ABL (T315I).

Dr. Pemovska and colleagues then tried to determine how the VEGFR inhibitor was active in inhibiting BCR-ABL1 (T315I). Compared with other BCR-ABL kinase inhibitors (like imatinib and dasatinib), axitinib was shown to fill different binding spaces – making the bond to the T3151 protein tighter.

“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said senior author Brion W. Murray, PhD, from Pfizer Worldwide Research and Development, the manufacturer of the drug. In the case of axitinib, it acts as two separate keys — one for renal cell carcinoma and one for leukemia.

“Our results on axitinib in T315I-mutant CML provide a powerful example of how unbiased drug sensitivity testing of patient-derived cancer cells can lead to the discovery of an unexpected drug-target interaction with mechanistic, structural, and clinical implications,” the authors concluded, adding that the results highlight the value of searching for novel indications for existing, emerging, and abandoned drugs.

As studies have not yet been conducted in people with CML or Ph+ ALL, safe and effective axitinib doses have not yet been established for this indication.


Reference
Pemovska T, Johnson E, Kontro M, et al. Axitinib effectively inhibits BCR-ABL1 (T315I) with a distinct binding conformation. Nature. 2015;519:102-05.

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