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【正文】 The best example of targeted cancer therapy) JNCI J Natl Cancer Inst (2023) 103 (7): 553561. Gleevec/Imatinib for Treating Chronic Myelogenous Leukemia (CML) NCI/NIH website A Small molecule inhibitor/ATP Competitor BCRABL BCRABL Imatinib 抗藥性 1. Activation of the BCRABL Independent pathways Breakpoint OD S/T kinase DBL SH3 SH2 N L S DNA BD ABD Y kinase BCR | ABL Ras pathway PI3K pathway JAK/STAT pathway Growth factor receptors Reactive oxygen species Tyr kinases/phosphatases and their substrates Cytoskeleton associated proteins … other targets Imatinib 抗藥性 1. Activation of the BCRABL Independent pathways (minor) 2. Mutations in ABL of BCRABL (major) Imatinib 抗藥性點(diǎn)突變體 Sawyers, Nature Medicine 15, 1158 1161 (2023) Dasatinib is highly active in most imatinibresistant BCRABL ABL Kinase Domain Imatinib Gate keeper抗藥性點(diǎn)突變體 (T315I) Csrc kinase domain T315I ABL Kinase Domain 產(chǎn)生空間位阻 失去氫鍵 T315I BCRABL is resistant to Imatinib and Dasatinib， but sensitive to Ponatinib. 乳腺癌 （ Breast Cancer） 1) The second leading cause of cancer death in woman with 400,000 death worldwide. 2) Three major types of breast cancer in clinic a) Luminal type (官腔） (~5070%): estrogen receptor (ER) and progestrone receptor (PR) (IHC for detection) b) Her2 positive (2025%): Her2/ErbB2 gene amplification (FISH for detection) c) Triple negative breast cancer (~15%) (TNBC) (三陰性乳腺癌） : ER, PR, and Her2 negative 3) Targeted Breast therapies a) Tamoxifen or aromatase inhibitor （ Letrozole) for ER+ breast cancer b) Herceptin or lapatinib for Her2+ breast cancer c) Only chemotherapy and radiation therapy for TNBC without targeted therapy Problems in Targeted Therapy for Breast Cancer and Management of TBNC: 1) Resistance to target therapies: Denovo resistance Acquired resistance 2) Only chemotherapy for TNBC (三陰性乳腺癌） : No targeted therapy Faster relapse and metastasis Has the highest death rate among all types of
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