Figure 1.

ALK downstream pathways and bypass signaling (A) Anaplastic lymphoma kinase (ALK) mediates signaling via the PI3K/AKT, RAS/MAPK, phospholipase Cγ (PLCγ) and Janus kinase (JAK)-signal transducer and activator of transcription (STAT); (B) ALK-independent resistance mechanism. Activation of bypass signaling pathways when ALK is inhibited with TKIs: EGFR activation, without EGFR mutations or amplifications; HER2 activation; c-KIT gene amplification in the presence of stem cell factor (SCF); MET activation bypassing ALK inhibitors without anti-MET activity; regulation via transcriptional of PDGFRβ and IGFR activation. Mutations in KRAS and copy number gain of wild-type KRAS; JM, Juxtamembrane.