fig1

Figure 1. We present our initial literature-based model of EGFR-mutation positive NSCLC tumor cells, treated with single TKIs, and the parallel compensatory pathways that are being activated. Upon TKI treatment the downstream PI3K/AKT and RAS/MAPK pathways - in light grey - are inhibited, limiting the ability of the cells for proliferation and survival. However, our previous work has shown that this inhibition is the direct cause of the activation of the JAK2/STAT3 and Src-YAP1 pathways, and cannot abrogate coexpressed RTKs (e.g., MET, CDCP1) on the cell membrane. This in turn causes increased cell proliferation and survival, and thus leads to therapy resistance. PIM is an important signaling node in this network, potentially activated through IL-6/STAT3 and/or hypoxia. PIM was shown to be activated in multiple tumor types, and may therefore provide a druggable target for various tumor types. EGFR: epidermal growth factor receptor; NSCLC: non-small cell lung cancer; TKI: tyrosine kinase inhibitor; PI3K: phosphatidylinositol 3-kinase; MAPK: mitogen-activated protein kinase; JAK2: Janus kinase 2; STAT3: signal transducer and activator of transcription 3; YAP1: Yes-associated protein 1; RTK: receptor tyrosine kinase; PIM: proviral integration site for Moloney murine leukemia virus; IL-6R: interleukin 6 receptor; CDCP1: CUB domain-containing protein 1; EphA2: EPH receptor A2; PXN: Paxillin