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

Xiaoling Song,Hui Zhong,Biao Jiang,Xiaojuan Qu,Linsong Yang

doi:10.1002/mco2.42

Xiaoling Song, Hui Zhong + Show 3 more

Open Access

https://doi.org/10.1002/mco2.42

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Journal: MedComm	Publication Date: Jun 17, 2021
Citations: 38	License type: CC BY 4.0

Affiliation: ShanghaiTech University, Changzhou University

Abstract

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.

Highlights

Lung cancer is the most common malignant cancer in the world, and it is the leading cause of cancer-related death
These results indicate that acquired aberrant anaplastic lymphoma kinase (ALK) protein alterations are the major source of drug resistance
Small and compact macrocyclic can bind completely inside the ATP pocket even in the presence of solvent front mutation and gatekeeper mutation. This empower them the ability to evade the resistance to previous generation ALK tyrosine kinase inhibitors (TKIs) drugs

Summary

INTRODUCTION

Lung cancer is the most common malignant cancer in the world, and it is the leading cause of cancer-related death. Treating ALK mutant cancer patients with targeted therapy greatly reduces toxic adverse effect and improves patients’ quality of life comparing to traditional chemotherapy.[3]. Five different ALK-Tyrosine kinase inhibitors (ALK-TKIs) have been approved by food and drug administration (FDA) to treat ALK-positive non-small cell lung cancer (NSCLC) patients (Figure 1). These drugs include the first-generation ALK-TKIs crizotinib, the secondgeneration ALK-TKIs ceritinib, alectinib and brigatinib, and the third generation ALK-TKIs lorlatinib. It is urgent to develop novel and effective treatment strategies to overcome drug resistance. This article was focused on the update on two novel strategies to overcome drug resistance

RESISTANCE MECHANISMS OF ALK KINASE INHIBITORS

NOVEL TREATMENT STRATEGIES

Develop smaller and more compact macrocyclic ALK-TKIs

Proteolysis targeting chimeras of ALK

Findings

CONCLUSIONS