Chemical structures of kinase inhibitors Sample Clauses

Chemical structures of kinase inhibitors. Structures for lapatinib, rapamycin, and the rapamycin analogue ridaforolimus (MK-8669) were downloaded from the ChemACX database (XxxxxxxxxXxxx, Xxxxxxxxx, XX) and drawn in ChemDraw (CambridgeSoft). Resistance to trastuzumab has been closely associated with increased PI3K signaling due to either loss of the PTEN phosphatase gene (Xxxxxx et al, 2004) or hyper-activating mutations in the PIK3CA catalytic subunit of PI3K (Xxxxx et al, 2007). Xxxxxx et al (Xxxxxx et al, 2010) recently showed that phosphorylation of Akt or the mTOR substrate p70S6K were not independently associated with trastuzumab resistance, but when considered together, p-Akt, p-p70S6K, and loss of PTEN were strongly associated with poor response to trastuzumab. A genome-wide loss-of-function short hairpin RNA screen performed to identify mediators of lapatinib resistance showed that loss of PTEN or PIK3CA mutations also contributed to lapatinib resistance (Xxxxxxx et al, 2008). Further, treatment with a dual inhibitor of PI3K/mTOR inhibited colony formation and proliferation of lapatinib- resistant cells harboring genetic defects in PI3K signaling (Xxxxxxx et al, 2008). In contrast, X’Xxxxx et al. (X’Xxxxx et al, 2010) suggested that lapatinib resistance was not associated with loss of PTEN or PIK3CA mutations, and that lapatinib could block the hyperactive PI3K signaling associated with trastuzumab resistance. Xxxx et al. (Xxxx et al, 2011) examined 57 primary tumor samples from lapatinib-treated patients with HER2- overexpressing breast cancer heavily pretreated with chemotherapy and trastuzumab. Patients with loss of PTEN or hyper-activating mutations in PIK3CA had a significantly lower clinical benefit rate (36.4% versus 68.6%) and significantly lower overall response rate (9.1% versus 31.4%) in contrast to those patients whose tumors did not show PI3K pathway activation. Blocking the PI3K pathway with mTOR inhibition has been demonstrated to be beneficial in trastuzumab-resistant cancers. Response rates of more than 40% and disease control rates of more than 70% were achieved in metastatic HER2-positive breast cancers resistant to trastuzumab and taxanes, when treated with trastuzumab, paclitaxel and everolimus (Xxxxx et al, 2010). The combination of trastuzumab, chemotherapy and everolimus has been demonstrated to be beneficial in patients with HER2-positive metastatic breast cancer, resistant to both trastuzumab and lapatinib. The use of mTOR inhibition, with everolimus, is currentl...