PMC:4307189 / 7569-9053 JSONTXT

{"project":"2_test","denotations":[{"id":"25599599-17892419-14868107","span":{"begin":80,"end":82},"obj":"17892419"},{"id":"25599599-18803986-14868108","span":{"begin":202,"end":204},"obj":"18803986"},{"id":"25599599-21385943-14868109","span":{"begin":301,"end":303},"obj":"21385943"},{"id":"25599599-21377448-14868109","span":{"begin":301,"end":303},"obj":"21377448"},{"id":"25599599-19671800-14868109","span":{"begin":301,"end":303},"obj":"19671800"},{"id":"25599599-21385943-14868110","span":{"begin":424,"end":426},"obj":"21385943"},{"id":"25599599-19671800-14868111","span":{"begin":607,"end":609},"obj":"19671800"},{"id":"25599599-21377448-14868112","span":{"begin":744,"end":746},"obj":"21377448"},{"id":"25599599-23542173-14868113","span":{"begin":1216,"end":1217},"obj":"23542173"},{"id":"25599599-22474259-14868114","span":{"begin":1218,"end":1219},"obj":"22474259"}],"text":"Lapatinib is a dual tyrosine kinase inhibitor of EGFR and ErbB2/HER2 receptors [12] that is used in combination therapy of ErbB2/HER2-positive breast cancer patients with advanced or metastatic tumors [13]. Several studies have examined the mechanism underlying lapatinib resistance at the molecular [14-16] and system level [17], active in HER2-positive breast cancer cell-lines through signaling pathways. Garrett et al. [14] reported over-expression of HER2 or HER3 in lapatinib-resistant SKBR3 and BT474 breast cancer cell lines. Over-expression of AXL tyrosine kinase was found in the BT474 cell-line [16], but interestingly a switched addiction from HER2 to FGFR2 pathway caused the UACC812/LR cell-line to become resistant to lapatinib [15]. Moreover, a detailed analysis of the global cellular network by Komurov et al. [17] revealed that up-regulation of the glucose deprivation response pathway compensates for the lapatinib inhibition in SKBR3 cell-line by providing an EGFR/ErbB2-independent mechanism of glucose uptake and survival [17]. Thus, the activation or up-regulation of compensatory pathways confers poor sensitivity of inhibitors (i.e. lapatinib resistance) in EGFR or ErbB2 targeted therapy [1,2,17]. The identification and analyses of potential cross-talks among the signaling pathways may provide deeper insights into the mechanism of drug resistance, and can facilitate finding a range of compensatory pathways for overcoming resistance in targeted therapy."}