Structural basis for drug resistance mechanisms against anaplastic lymphoma kinase

Abstract

Drug resistance to anaplastic lymphoma kinase (ALK) inhibitors (crizotinib and ceritinib) is caused by mutation in the region encoding kinase domain of ALK. Compounds with potential ability to inhibit all strains of ALK are a solution to tackle the problem of drug resistance. In this study, we delineated positions of residues possessing the ability to make ALK drug resistant upon mutation by assessing them using five parameters (conservation index, binding-site root-mean-square deviation, protein structure stability, change in ATP, and drug-binding affinity). Four residual positions (Leu 1122, Thr 1151, Phe 1245, and Gly 1269) were ascertained. This study will be beneficial for designing drugs with better proficiency against ALK and the issues of drug resistance. This study can be taken as a pipeline for investigating drug-resistant mutations in other diseases as well.

Enhancing Lung Cancer Care in Portugal: Bridging Gaps for Improved Patient Outcomes

“…ALK-dependent resistance hinders the binding of the drug to the active site and approximately one-third of ALK-positive tumours treated with crizotinib develop some of these alterations. The first mutation of this type to be described was L1196M; however, there are others, such as G1269A, G1202R, and F1174 [48,64,65]. On the other hand, ALK-independent resistance is related to the aberrant activation of other kinases, such as EGFR, SRC, and MEK/ERK [66].…”

PROTACs: A novel strategy for cancer drug discovery and development

“…Therefore, targeting ALK fusion proteins is an emerging and effective target for the treatment of cancer, especially NSCLC 299 . However, the durability of clinical efficacy of ALK tyrosine kinase inhibitors in NSCLC is often limited by drug resistance within 1−2 years, partly due to acquired ALK resistance mutations 300,301 . Therefore, new effective treatment strategies are needed to overcome the defects of clinical resistance to ALK inhibitors.…”

“…299 However, the durability of clinical efficacy of ALK tyrosine kinase inhibitors in NSCLC is often limited by drug resistance within 1−2 years, partly due to acquired ALK resistance mutations. 300,301 Therefore, new effective treatment strategies are needed to overcome the defects of clinical resistance to ALK inhibitors. In 2020, the Jiang group developed a series of ALK degraders based on ALK inhibitor Alectinib and lenalidomide (Figure 3; CRBN-3).…”