Table 4 Main mechanisms involved in acquired resistance to EGF receptor-tyrosine kinase inhibitors and the associated targetable drugs

HER2 amplification

Afatinib, Trastuzumab, ado-trastuzumab emtansine (TDM1)

MET overexpression/genetic alteration

● Anti-HGF antibody: Rilotumumab, Ficlatuzumab

● Anti-c-MET antibody: MET Mab, Emibetuzumab (LY2875358)

● Selective c-MET inhibitor: Tivantinib (ARQ197), Capmatinib (INC280),

            Savolitinib (AZD6094), Tepotinib (EMD 1214063),

            SGX523, SAR125844,

● Multikinase inhibitors: Crizotinib, Cabozantinib (XL184), Glesatinib (MGCD265),

           Merestinib (LY2801653), S49076

PIK3CA

PI3K-AKT-mTOR

● PI3K inhibitor: Pilaralisib (XL147), Dactolisib (BEZ235) and Pictilisib (GDC-0941),

        Buparlisib (BKM120)

● AKT inhibitor: MK-2206

● mTOR inhibitor: Everolimus, Temsirolimus, Ridaforolimus

BRAF

Ras-Raf-MEK-ERK

Vemurafenib (PLX4032), Dabrafenib (GSK2118436), Selumetinib, LY3009120

AXL overexpression

GAS6-AXL

● Tyrosine kinase inhibitor: Cabozantinib (XL 184)

● AXL antibody: E8, D9, Mab173

● AXL decoy receptor: AXL-Fc, MYDI