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. 2012 Jul 6;109(31):E2127–E2133. doi: 10.1073/pnas.1203530109

Fig. P1.

Fig. P1.

Cell-proliferative signaling pathways in lung tumors. EGFRs signal through the PI3K/AKT and RAS/MEK/ERK cascades. (i) WT EGFRs are activated in a ligand-dependent manner. (ii) Mutant EGFRs are constitutively activated. EGFR TKIs block kinase activity from mutant EGFRs and inhibit downstream signaling. (A and D) Acquisition of NRAS or BRAF mutations (mts) leads to constitutive activation of the RAS/MEK/ERK pathway. (B and E) EGFR-TKIs inhibit EGFR, but mutant NRAS or BRAF maintain downstream ERK activation. (C) The combination of EGFR and MEK inhibitors can overcome resistance caused by the acquisition of NRAS mutations in EGFR-mutant cells. (F) The combination of EGFR and BRAF inhibitors or EGFR and MEK inhibitors can overcome resistance caused by the acquisition of BRAF mutations in EGFR-mutant cells.