PMC:4307189 / 5444-7568 JSONTXT

{"project":"2_test","denotations":[{"id":"25599599-23542173-14868101","span":{"begin":318,"end":319},"obj":"23542173"},{"id":"25599599-22751098-14868102","span":{"begin":756,"end":757},"obj":"22751098"},{"id":"25599599-23091115-14868102","span":{"begin":756,"end":757},"obj":"23091115"},{"id":"25599599-22956644-14868102","span":{"begin":756,"end":757},"obj":"22956644"},{"id":"25599599-17463250-14868102","span":{"begin":756,"end":757},"obj":"17463250"},{"id":"25599599-20028874-14868102","span":{"begin":756,"end":757},"obj":"20028874"},{"id":"25599599-23542173-14868103","span":{"begin":967,"end":968},"obj":"23542173"},{"id":"25599599-23542173-14868104","span":{"begin":1458,"end":1459},"obj":"23542173"},{"id":"25599599-23542173-14868105","span":{"begin":1820,"end":1821},"obj":"23542173"},{"id":"25599599-21531565-14868106","span":{"begin":2120,"end":2122},"obj":"21531565"}],"text":"Cross-talk among signaling pathways may play a vital role in cancer drug resistance, especially in receptor targeted therapies. For example, in EGFR/HER2 signaling pathways, cross-talk with other signaling pathways may occur at various levels of signal transduction: receptor level, mediator level and effector level [1]. At the receptor level, other RTKs (receptor tyrosine kinases) having common downstream targets of EGFR/HER2 may become involved in cross-talk with EGFR/HER2 signaling pathways. In many cancers, these alternative RTKs including MET, IGF1R, FGFR and EphA2 become activated or amplified in order to maintain the signals for cell survival and/or proliferation in common downstream pathways, thus nullifying the inhibition of EGFR kinase [6-10]. Cross-talk at mediator level includes the activation/inactivation of major components of mediator pathways by mutation/deletion of oncogenic driver genes, which eventually activates downstream effectors [1]. These constitutive activations/inactivations of mediator pathways are independent of receptors. The effect of signaling cross-talk in drug resistance at effector level is more complex and diverse since there may be numerous effectors of RTKs signaling pathways. Resistance at the effector level may occur when some critical effectors (i.e. TSC, FOXO3) involved in cell survival and proliferation show an altered phenotype caused by other signaling pathways via RTK signaling cross-talk [1]. Additionally, inhibitor sensitivity can be affected by cross-talk between signaling pathways triggered by the targeted RTK and other signaling pathways (triggered by other RTKs). For example, the EGFR/HER2 signaling pathway can cross-talk with Wnt/ β-catenin, Notch, and TNF α/IKK/NF- κB signaling pathways to affect the EGFR/HER2 inhibitors’ sensitivities [1]. Cross-talk between effector pathways and feedback inhibition is also responsible for the adaptive and dynamic response of cancer cells against inhibitor therapies, for example, compensating the inhibited components to maintain key downstream functions, such as cell survival, proliferation etc. [11]."}