J Cancer 2019; 10(11):2488-2500. doi:10.7150/jca.29528 This issue
Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
The BCR-ABL fusion protein with strong tyrosine kinase activity is one of the molecular biological bases of leukemia. Imatinib (Gleevec), a specific targeted drug for the treatment of chronic myeloid leukemia (CML), was developed for inhibiting the kinase activity of the BCR-ABL fusion protein. Despite the positive clinical efficacy of imatinib, the proportion of imatinib resistance has gradually increased. The main reason for the resistance is a decrease in sensitivity to imatinib caused by mutation or amplification of the BCR-ABL gene. In response to this phenomenon, the new generation of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion protein was developed to solve the problem. However this strategy only selectively inhibits the tyrosine kinase activity of the BCR-ABL protein without eliminating the BCR-ABL protein, it does not fundamentally cure the BCR-ABL-positive leukemia patients. With the accumulation of the knowledge of cellular molecular biology, it has become possible to specifically eliminate certain proteins by cellular proteases in a specific way. Therefore, the therapeutic strategy to induce the degradation of the BCR-ABL fusion protein is superior to the strategy of inhibiting its activity. The protein degradation strategy is also a solution to the TKI resistance caused by different BCR-ABL gene point mutations. In order to provide possible exploration directions and clues for eliminating the BCR-ABL fusion protein in tumor cells, we summarize the significant molecules involved in the degradation pathway of the BCR-ABL protein, as well as the reported potent compounds that can target the BCR-ABL protein for degradation.
Keywords: BCR-ABL fusion protein, Tyrosine kinase activity, Inhibitor, Protein degradation