Two novel strategies to overcome the resistance to ALK tyrosine kinase inhibitor drugs: Macrocyclic inhibitors and proteolysis‐targeting chimeras

Lung cancer is the most malignant tumor in the worldwide. About 3%‐5% non‐small cell lung cancer (NSCLC) patients carry anaplastic lymphoma kinase (ALK) gene fusions and receive great benefits from ALK‐targeted therapy. However, drug resistance inevitably occurs even with the most potent inhibitor drug lorlatinib. About half of the resistance are caused by alteration in ALK proteins for earlier ALK TKI drugs and near one‐third of loratinib resistant cases are caused by compound mutations without current effective treatment strategy in clinic. Novel strategies are in great need to overcome drug resistance. Lately, two novel strategies have been developed and attracted great attentions for their potentials to overcome drug resistance problems: (1) developed small compact macrocyclic ALK kinase inhibitors and (2) developed ALK targeted proteolysis‐targeting chimera (PROTAC) drugs. The macrocyclic molecules are small and compact in size, brain barrier permeable, and highly potent against lorlatinib‐resistant compound mutations. Developed ALK targeted PROTAC molecules could degrade oncogenic ALK driver proteins. Some showed superiority in killing ALK positive cancer cells and inhibiting the growth of cells expressing G1202R resistant ALK proteins comparing to inhibitor drugs. The update on these two treatment strategies was reviewed. Acquired resistance mutations including G1202R and L1196M, alone or in compound form, in ALK proteins lead to drug resistance to ALK‐targeted therapy. Two novel strategies showed great potential in overcoming such resistance: (1) More effective inhibition by small and compact macrocyclic inhibitors; (2) Degradation of oncogenic ALK proteins including those with resistant mutations by ALK targeted proteolysis‐targeting chimeras.