HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways.

摘要: Anti-HER2 antibody trastuzumab is emerging as a frontline therapy for patientswith metastatic breast cancers that overexpress HER2. Understanding the molecularmechanisms by which inhibits tumor growth should permit design ofeven more effective trastuzumab-based protocols. Several groups including our own havedemonstrated induction of cyclin-dependent kinase (CDK) inhibitor p27Kip1 protein isone key mechanisms action HER2-targeting antibodies. In this review, wediscuss currently available data regarding multiple signaling targets and pathways bywhich antibodies upregulate in cancer cells thatoverexpress HER2-mediated cancercells, ultimately upregulating levels activity protein. At least sixsignaling are modulated trastuzumab. By inhibiting CDK2 anddecreasing Thr187 phosphorylation p27Kip1, abrogates targeting SCFubiquitinE...