Fig. 6: Schematic model showing proposed mechanism of action of afatinib and crizotinib combination treatment. | Cell Death & Disease

Fig. 6: Schematic model showing proposed mechanism of action of afatinib and crizotinib combination treatment.

From: Inhibiting insulin and mTOR signaling by afatinib and crizotinib combination fosters broad cytotoxic effects in cutaneous malignant melanoma

Fig. 6

Combination treatment with afatinib and crizotinib blocks IRS-1and downstream effector pathways like AKT and RAS. Downstream mediators of the mTOR pathway- RPS6KB1 and RPS6 are also inhibited by the combination. Co-silencing of IRS-1 and RPS6 potentiates apoptotic cell death and ablates cellular proliferation. RTKs previously associated with BRAFi resistance like AXL and EPHA2 are downregulated in the combination resistance cell line, whereas the catalytic subunit of PI3K (p85) is upregulated.

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