Fig. 2: Examples of Resistance Mechanisms and Treatment Strategies for ALK inhibitor resistant tumors.
From: ALK fusions in the pan-cancer setting: another tumor-agnostic target?
This figure Illustrates mechanisms of development of resistance to ALK inhibitors and possible management strategies. For example, development of bypass pathways like EGFR, MET, PDGFR, IGF-1R, CDK, mTOR and SHP2 can lead to resistance and can be targeted by their respective inhibitors. Resistance can also develop because of epigenetic modifications and other immunomic changes in tumor, which may theoretically be targeted by heat shock protein (HSP) 90 inhibitors, Cluster differentiation (CD) 30 inhibitors and immune check point inhibitors. Similarly, formation of ALK amplifications may also be a mechanism of resistance and can be treated with chemotherapy. This figure also illustrates various acquired tyrosine kinase domain mutations which can be targeted by different generations of ALK inhibitors. The mutations listed on the left of ALK kinase domain are sensitive to respective ALK tyrosine kinase inhibitors. For example, crizotinib inhibits G1123S, L1198F resistant mutation. Ceritinib inhibits I1171T, I1171N, V1180L, S1206C, S1206Y, G1269A. Alectinib inhibits i1151Tins, G1123S, L1152P, C1156Y, F1174C, F1174L, F1174V, L1196M, S1206C, S1206Y, G1269A resistant mutations. Brigatinib inhibits i1151Tins, L1152P, C1156Y, I1171T, I1171N, I1171S, F1174C, F1174L, F1174V, V1180L, L1196M, S1206Y, G1269A and Lorlatinib inhibits i1151Tins L1152P, C1156Y, I1171T, I1171N, I1171S, F1174C, F1174L, F1174V, V1180L, L1196M, S1206C, S1206Y, E1210K, G1269A, E1210K, G1202R, E1210K, F1245C. Created by Biorender.com.
