fig4

Figure 4. Obtained model of EGFR-mutation positive NSCLC tumor cells, after dual EGFR- (osimertinib) and PIM- (AZD1208) inhibition. Upon osimertinib treatment, the downstream PI3K/AKT and RAS/MAPK pathways - in light grey - are inhibited, lowering cell proliferation and survival. However, AZD1208 treatment now blocks both the activation of PIM and the activation of the JAK/STAT3 pathway. This leads to moderate synergistic effects in vitro. However, the Src-YAP1 pathway is still activated (PC9) or only slightly inhibited (H1975), and can therefore compensate for the blockade induced by osimertinib and AZD1208. EGFR: epidermal growth factor receptor; NSCLC: non-small cell lung cancer; PIM: proviral integration site for Moloney murine leukemia virus; 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; CDCP1: CUB domain-containing protein 1; IL-6R: Interleukin 6 receptor; PXN: Paxillin