Table 1. EGFR-dependent resistance mechanisms of irreversible EGFR-TKIs and potential treatment strategies.
| Resistant mechanisms | Drugs | Co-existed mechanism | Strategies | Reference |
|---|---|---|---|---|
| 2G-TKIs | ||||
| T790M | HKI-272, afatinib | - | 3G-TKIs Cetuximab plus afatinib | [10, 14, 15] [21–24] |
| T790M amplification | Dacomitinib | EGFR amplification | - | [17] |
| V843I | Afatinib, dacomitinib | - | - | [30, 31] |
| C797S | Afatinib, HKI-272 | - | 1G-TKIs | [29], [10] |
| C797S/G G796R/C/D L718A M766T T854A |
Canertini(CI-1033) | - | - | [27] |
| E931G | CL-387,785 | - | - | [28] |
| L792F | Afatinib | - | Dacomitinib | [29] |
| 3G-TKIs | ||||
| C797S | AZD9291, WZ4002, CO-1686 | - | Quinazoline based EGFR-TKIs | [32] |
| T790M/C797S | AZD9291, WZ4002 CO-1686, HM-61713 | C-Met amplification,KRAS G12S mutation | 3G-TKIs + 1G-TKIs (in trans allele) Chemotherapy (in cis allele) Cetuximab (L858R/T790M/C797S) EAI045+cetuximab (L858R/T790M/C797S) Brigatinib+ anti-EGFR antibody CUDC-101 (a EGFR/HER2/HDAC inhibitor) PKC412 (a broad spectrum protein kinase inhibitor) |
[32–37, 39–42] |
| L718Q L844V |
WZ4002, CO-1686 | - | Quinazoline based EGFR-TKIs AZD9291 |
[32] |
| G796D | AZD9291 | T790M loss | - | [169] |
| T790M/L718Q T790M/L844V |
AZD9291, WZ4002, CO-1686 | - | - | [32, 38] |
| T790M/L798I T790M/L692V T790M/E709K |
CO-1686 | - | - | [35] |
| T790M/C797G | EGFR amplification | - | [170] | |
| T790M/L792F/Y/H, T790M/L718Q/V, T790M/G796S/R | AZD9291 | T790M (in cis)/C797S (in trans) | - | [45], [43], [44] |
| T790M/G724S | EGF816 | T790M loss | - | [61] |
| EGFR amplification | AZD9291, CO-1686 | Src-AKT activation KRAS G13D EMT T790M/C797G, |
CO-1686+Cetuximab Afatinib+Cetuximab |
[35, 46–48] |
“-”represents no co-existed mechanisms or no treatment strategies, 1G-TKIs: first-generation EGFR-TKIs; 2G-TKIs: second generation EGFR-TKIs; 3G-TKIs: third-generation EGFR-TKIs.