title: The erbB3- and IGF-1 receptor-initiated signaling pathways exhibit distinct effects on lapatinib sensitivity against trastuzumab-resistant breast cancer cells.
abstract: Both erbB3 and IGF-1 receptor (IGF-1R) have been shown to play an important role in trastuzumab resistance. However, it remains unclear whether erbB3- and IGF-1R-initiated signaling pathways possess distinct effects on the sensitivity of lapatinib, a dual tyrosine kinase inhibitor against both EGFR and erbB2, in trastuzumab-resistant breast cancer. Here, we show that the trastuzumab-resistant SKBR3-pool2 and BT474-HR20 breast cancer sublines, as compared the parental SKBR3 and BT474 cells, respectively, exhibit refractoriness to lapatinib. Knockdown of erbB3 inhibited Akt in SKBR3-pool2 and BT474-HR20 cells, significantly increased lapatinib efficacy, and dramatically re-sensitized the cells to lapatinib-induced apoptosis. In contrast, specific knockdown of IGF-1R did not alter the cells' responsiveness to lapatinib. While the levels of phosphorylated Src (P-Src) were reduced upon IGF-1R downregulation, the P-Akt levels remained unchanged. Furthermore, a specific inhibitor of Akt, but not Src, significantly enhanced lapatinib-mediated anti-proliferative/anti-survival effects on SKBR3-pool2 and BT474-HR20 cells. These data indicate that erbB3 signaling is critical for both trastuzumab and lapatinib resistances mainly through the PI-3K/Akt pathway, whereas IGF-1R-initiated Src activation results in trastuzumab resistance without affecting lapatinib sensitivity. Our findings may facilitate the development of precision therapeutic regimens for erbB2-positive breast cancer patients who become resistant to erbB2-targeted therapy.
authors.affiliation: Cancer Research Institute and Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.|Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Lyu
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, NC, USA.
authors.forename: Xiao He
authors.initials: XH
authors.lastname: Yang
authors.affiliation: Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Edgerton
authors.affiliation: Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Ann D
authors.initials: AD
authors.lastname: Thor
authors.affiliation: Department of Pathology, Xiangya Hospital, School of Basic Medical Science, Central South University, Changsha, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wu
authors.affiliation: Cancer Research Institute and Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: He
authors.affiliation: Cancer Research Institute and Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.|Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Bolin
authors.initials: B
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C583557:IGF1 protein, human; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib; D007334:Insulin-Like Growth Factor I; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; D017526:Receptor, IGF Type 1; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; D000068878:Trastuzumab
keywords: IGF-1R; erbB3; lapatinib; resistance; trastuzumab