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![Emerging actionable targets to treat therapy-resistant colorectal cancers](https://image.oaes.cc/fc437890-15d0-49de-819c-c6e0fd0507b6/4465.fig.2.jpg)
Figure 2. Mechanisms of resistance to targeted therapy against EGFR and mutated BRAF. Intrinsic resistance to EGFR blockade by panitumumab (Pani) and cetuximab (Cetu) occurs in case of activating mutations in the EGFR and its downstream effectors such as RAS, BRAF, and PIK3CA and when there is loss of PTEN either due to truncation or deletion. Acquired resistance stems from stimulation of collateral pathways impinging on the same downstream signaling activated by EGFR (i.e., the RAS/MAPK and the PIK3/AKT pathways). Hyperactivation of these pathways may be due to overexpression or mutation of ERBB2, heterodimerization of ERBB2 and ERBB3, engagement of the EGFR by TGFA which in turn activates MET, MET overexpression, EPHA2 overexpression, or IGF1R engagement. Strategies to overcome the insensitivity to EGFR blockade are directed at the inhibition of the collateral signaling such as using ERBB2 blocking agents trastuzumab (Trast) and lapatinib (Lapa) and the MET inhibitors crizotinib (Crizo) and capmatinib (Cap). Resistance to the mutated BRAF inhibitor vemurafenib (Vemu) originates from the shifting in the choice of the dimerization companion. In the resistant cells instead of mutated BRAF homodimers, mutated BRAF/CRAF heterodimers are formed which are insensitive to the inhibitor and thus MAPK activation is refueled. To prevent hetodimerization a novel inhibitor, that specifically bind mutated BRAF homodimers has been developed. Another route of escape to mutant BRAF blockade has been described where activation of the WNT/β-catenin signaling is triggered via FAK. Both MAPK and β-catenin signaling eventually activate a series of transcription factors (TFs) responsible for the transcription of proliferative genes. Currently, to prevent resistance to BRAF inhibition, a vertical blockade of the pathway is being tested in clinical trials using vemurafenib in combination with a MEK inhibitor such as cobimetinib (Cobi) or trametinib (Trame). Mutated proteins are indicated by the red stars and the italicized name.