变构抑制增强了 ABL 激酶抑制剂靶向未突变 BCR-ABL 和 BCR-ABL-T315I 的疗效。

BACKGROUND

Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses BCR to ABL resulting in deregulated ABL-tyrosine kinase activity. The constitutively activated BCR/ABL-kinase "escapes" the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. The ABL-kinase inhibitors (AKIs) Imatinib, Nilotinib or Dasatinib, which target the ATP-binding site, are effective in Ph + leukemia. Another molecular therapy approach targeting BCR/ABL restores allosteric inhibition. Given the fact that all AKIs fail to inhibit BCR/ABL harboring the 'gatekeeper' mutation T315I, we investigated the effects of AKIs in combination with the allosteric inhibitor GNF2 in Ph + leukemia.

METHODS

The efficacy of this approach on the leukemogenic potential of BCR/ABL was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in patient-derived long-term cultures (PDLTC) from Ph + ALL-patients.

RESULTS

Here, we show that GNF-2 increased the effects of AKIs on unmutated BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner.

CONCLUSIONS

Our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants using a combination of AKIs and allosteric inhibitors.

背景

慢性髓系白血病（CML）和费城染色体阳性（Ph+）急性淋巴细胞白血病（Ph+ALL）是由 t（9；22）引起的，该易位导致 BCR 与 ABL 融合，从而导致 ABL 酪氨酸激酶活性失调。组成性激活的 BCR/ABL-激酶“逃避”了 c-ABL 的自动抑制机制，如变构抑制。靶向 ATP 结合位点的 ABL-激酶抑制剂（AKIs）伊马替尼、尼罗替尼或达沙替尼在 Ph+白血病中有效。另一种靶向 BCR/ABL 的分子治疗方法恢复变构抑制。鉴于所有 AKIs 都不能抑制携带“门控”突变 T315I 的 BCR/ABL，我们研究了 AKIs 与变构抑制剂 GNF2 联合在 Ph+白血病中的效果。