Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive
Aya Shiba-Ishii1, Ted W Johnson2, Ibiayi Dagogo-Jack1,3
1Massachusetts General Hospital Cancer Center, Charlestown, MA, USA.
Abstract:
Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors.
Insights
Lorlatinib resistance in ALK-positive lung cancer is often driven by specific mutations. New lorlatinib analogs show promise in overcoming these resistance mechanisms, offering new precision therapy strategies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Lorlatinib is a potent anaplastic lymphoma kinase (ALK) inhibitor for ALK-positive non-small cell lung cancer.
- Emergence of compound ALK mutations leads to therapeutic resistance against lorlatinib.
Purpose of the Study:
- To identify the spectrum of compound ALK mutations causing lorlatinib resistance.
- To develop novel lorlatinib analogs targeting these resistance mutations.
Main Methods:
- Analysis of patient-derived lorlatinib-resistant ALK mutations.
- Design and synthesis of structurally diverse lorlatinib analogs.
- In vitro evaluation of analog potency against specific ALK mutations.
Main Results:
- The majority of lorlatinib-resistant mutations identified were ALK G1202R or I1171N/S/T.
- Structurally diverse lorlatinib analogs demonstrated differential selectivity against G1202R and I1171N/S/T mutations.
- Structural analysis confirmed enhanced inhibition of mutant kinases by the novel analogs.
Conclusions:
- A classification of heterogeneous ALK compound mutations is proposed.
- Development of distinct therapeutic strategies for precision targeting is enabled.
- Novel lorlatinib analogs offer potential for overcoming resistance in ALK-positive lung cancer.
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