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. 2017 Sep 22;8(52):90557–90578. doi: 10.18632/oncotarget.21164

Figure 2. EGFR-independent resistance mechanisms of irreversible EGFR-TKIs.

Figure 2

EGFR phosphorylation still can be blocked by EGFR-TKIs, but downstream pathways of EGFR remain activated. The activation of other RTKs (c-Met, HER2, IGF1R, FGFR1, etc.) or the aberrant activation of downstream pathways (KRAS gain/mutation, NRAS gain/mutation, BRAF mutation, MAPK1 amplification, PIK3CA mutation, AKT3 activation, PTEN deletion) offer a way bypass EGFR to reactivate of MAPK and PI3K-AKT signaling leading to the proliferative and anti-apoptotic effect. The activation of downstream signaling is uncoupled from upstream EGFR activation in EGFR-independent resistant cells.