Story of Bcr Abl continues

Though personalized therapy or pretreatment is heated in 2010s after Angelina Jolie's choice of double mastectomy on BRCA1 positivity, it has a long history however. Oncologists will not forget the lesson of Bcr-Abl, the first successful target of personalized cancer therapy. Because the fusion chromosome (Chr.9-22, Philadelphia Chromosome) and the corresponding fusion gene/protein Bcr-Abl were discovered in as early as 1960s-1970s, PP242 but the first small molecule (named STI571, later Imatinib) that specifically inhibit Bcr-Abl kinase was invented in as late as 1990s. "Companion test" was subsequently recognized and used in oncology.
From then on, tumor mechanism study (as is cell signaling study) prospers. Many tyrosine kinases other than ABL were found aberrant in tumor tissues, leading to TKI development rash. Nearly all of tyrosine kinases signals through PI3K-AKT-mTOR axis. Other successful examples are small molecule inhibitors (such as Gefitinib) AZD2281 targeting EGFR and its mutations.
But Bcr-Abl IS unique! It directly phosphorylates CRKL/CBL/CRK complex, Grb2/Shc and STAT5, which, respectively, activates PI3K, ras and Bcl-XL. A single mutation of T315I made Bcr-Abl even more stimulatory and drug-resistant. Drug makers are combating this well-known tiger still. For example, HS-438, a specific Bcr-Abl T315I inhibitor, is just reported in March 2014. Meanwhile, AURKA and AURKB, two cell cycle kinase, are found activated by Bcr-Abl/Akt axle. Thus, MLN8237, an Aurora kinase inhibitor, shall be a hopeful drug candidate in CML too.

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