TABLE 1.
Cancer specific ERK5-activating resistance mechanisms following RAF-MEK1/2-ERK1/2 targeting.
| Cancer type | Genomic alteration supporting ERK1/2 pathway activation | Ineffective targeting (pharmacological/genetic inhibition) | ERK5-activating resistance mechanism | Effective combined targeting strategies | References |
| Colorectal cancer | K-RAS mutation | MEK1/2 (PD0325901) or ERK1/2 (KO) | Increased phosphorylation/activation of ERK5 likely due to DUSP deregulation | MEK1/2i + ERK5i (in vitro) | de Jong et al., 2016 |
| Neuroblastoma | ALK mutation/amplification | MEK1/2 (Trametinib) | Increased activation of AKT-ERK5 signaling | MEK1/2i + ERK5i or AKTi (proposed) | Umapathy et al., 2017 |
| Pancreatic ductal adenocarcinoma | K-RAS mutation | MEK1/2 (Selumetinib, Trametinib); ERK1/2 (SCH772984) | Upregulation of EGFR-SRC-ERK5 pathway | ERK1/2i + ERK5i (in vivo) | Vaseva et al., 2018 |
| Non-small-cell lung carcinoma | K-RAS mutation | MEK1/2 (Cobimetinib) | Increased phosphorylation/activation of ERK5 likely dependent on RTKs | MEK1/2i + ERK5i or ERK5-KO (in vitro) or ERK5-KD (in vitro and in vivo) | Dompe et al., 2018 |
| Melanoma | N-RAS mutation | MEK1/2 (Trametinib); ERK1/2 (GDC-0994) | Increased phosphorylation/activation of ERK5 likely dependent on PDGFRβ | ERK1/2i + ERK5i (in vitro); MEK1/2i + ERK5i (in vitro and in vivo) | Adam et al., 2020 |
| Melanoma | BRAF mutation | BRAF + MEK1/2 (Vemurafenib + Trametinib) | Increased phosphorylation/activation of ERK5 mediated by SRC-MEK5 cascade | BRAFi/MEK1/2ì + ERK5-KD (in vitro) or ERK5i (in vitro and in vivo) | Song et al., 2017 |
| Melanoma | BRAF mutation | BRAF + MEK1/2 (Vemurafenib + Trametinib); BRAF + ERK1/2 (Vemurafenib + SCH772984) | Upregulation of IGF1R-MEK5-ERK5 pathway | ERK1/2i + IGF1Ri (in vivo) | Benito-Jardón et al., 2019 |
| Melanoma | BRAF mutation | BRAF (Vemurafenib); MEK1/2 (PD0325901) | Increased phosphorylation/activation of ERK5 mediated by miR-211 | Lee et al., 2020 |
KO, knock-out; KD, knock-down (shRNA).