Prediction of Resistance Mutations Against Upcoming Anaplastic Lymphoma Kinase Inhibitors

Doi, Yuta; Tagaya, Hiroaki; Noge, Ayaka; Semba, Kentaro

doi:10.1007/s11523-022-00919-5

Cited by 5 publications

(5 citation statements)

References 33 publications

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“…In this case, the patient experienced a PR and got a PFS of only 5 months. In previous studies, ALK G1202R has been shown to be resistant to ensartinib in patients with lung cancer ( 12 , 13 ), while I1171N was sensitive to ensartinib in cell lines ( 14 ). Here, we found that co-mutation of ALK I1171N and G1202R was resistant to ensartinib.…”

Section: Discussionmentioning

confidence: 90%

Acquired ALK G1202R-, ALK I1171N-, or EML4-ALK-mediated resistance to ensartinib in lung adenocarcinoma but responded to lorlatinib: A case report

Guo

2023

Front. Oncol.

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ALK rearrangements are identified as driver mutations in non-small-cell lung cancer (NSCLC). EML4 is the most common partner of ALK rearrangements. Here, we reported a patient with lung adenocarcinoma who was identified with EML4-ALK mutations when he progressed on an immune checkpoint inhibitor. The patient was treated with alectinib and obtained a progression-free survival (PFS) of 24 months. Then, next-generation sequencing on circulating tumor DNA identified multiple ALK mutations, including ALK G1202R, I1171N, ALK-ENC1, and EML4-ALK. Ensartinib was given, and the patient achieved a PFS of 5 months. After progression, lorlatinib was administered, and the patient achieved a partial response. Now, the benefit is still ongoing with a PFS over 10 months. Our case may provide evidence for the treatment choice of multiple ALK mutations, including ALK I1171N.

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Section: Discussionmentioning

confidence: 90%

Acquired ALK G1202R-, ALK I1171N-, or EML4-ALK-mediated resistance to ensartinib in lung adenocarcinoma but responded to lorlatinib: A case report

Guo

2023

Front. Oncol.

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“…FEP has a unique advantage in quantitatively predicting the binding free energies of SMKIs and WT/mutant kinase, and therefore it can help medicinal chemists examine their design ideas before experimental validation. AI predictive methods, together with physics-based modeling and experimental prediction of resistance mutations, can predict the gatekeeper mutations of new drug targets and provide a useful forecast to aid in the discovery of resistance-causing gatekeeper mutations. − AI generative models for generating new chemical structures are expected to expand the chemical space and provide new ideas for the design of SMKIs targeting gatekeeper mutations. , By incorporating medicinal chemists’ creativity with these new drug types and intelligent technologies, it is believed that targeting gatekeeper mutations will become a new paradigm in kinase drug development.…”

Section: Discussionmentioning

confidence: 99%

Targeting Gatekeeper Mutations for Kinase Drug Discovery

et al. 2022

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Clinically acquired resistance is a major challenge in cancer therapies with small-molecule kinase inhibitors (SMKIs). Gatekeeper mutations in the ATP-binding pocket of kinases are the most common mutations leading to acquired resistance. To date, seven new-generation kinase inhibitors targeting gatekeeper mutations have been approved by the FDA; however, the clinical need is still unmet. Here, we systematically summarize the types of gatekeeper mutations across the kinase family, the structural basis for acquired resistance, and newly developed SMKIs targeting gatekeeper mutations as well as highlight the opportunities and challenges of kinase drug discovery for targeting gatekeeper mutations.

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“…In another study, G1202R and I1171N mutants (alectinib-resistant) showed sensitivity to repotrectinib and ensartinib in Ba/F3 cells, respectively. The authors also predicted repotrectinib resistance mutations (G1202R + L1196M, F1174C/L/I, E1129V/K, C1156Y) (Doi et al, 2022).…”

Section: Anaplastic Lymphoma Kinase Inhibitors-resistance Mechanismsmentioning

confidence: 99%

“…Novel ALK TKIs represent a promising perspective regarding the compound mutations. For instance, Doi et al showed that TPX-0131 inhibits mutations composed of G1202R with L1196M, E1129V, and C1156Y (Doi et al, 2022).…”

Section: Anaplastic Lymphoma Kinase Inhibitors-resistance Mechanismsmentioning

confidence: 99%

Anaplastic lymphoma kinase inhibitors—a review of anticancer properties, clinical efficacy, and resistance mechanisms

Kiełbowski,

Żychowska,

Becht

2023

Front. Pharmacol.

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Fusions and mutations of anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor, have been identified in several neoplastic diseases. Rearranged ALK is a driver of tumorigenesis, which activates various signaling pathway associated with proliferation and survival. To date, several agents that target and inhibit ALK have been developed. The most studied ALK-positive disease is non-small cell lung cancer, and three generations of ALK tyrosine kinase inhibitors (TKIs) have been approved for the treatment of metastatic disease. Nevertheless, the use of ALK-TKIs is associated with acquired resistance (resistance mutations, bypass signaling), which leads to disease progression and may require a substitution or introduction of other treatment agents. Understanding of the complex nature and network of resistance mutations may allow to introduce sequential and targeted therapies. In this review, we aim to summarize the efficacy and safety profile of ALK inhibitors, describe off-target anticancer effects, and discuss resistance mechanisms in the context of personalized oncology.

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Prediction of Resistance Mutations Against Upcoming Anaplastic Lymphoma Kinase Inhibitors

Cited by 5 publications

References 33 publications

Acquired ALK G1202R-, ALK I1171N-, or EML4-ALK-mediated resistance to ensartinib in lung adenocarcinoma but responded to lorlatinib: A case report

Acquired ALK G1202R-, ALK I1171N-, or EML4-ALK-mediated resistance to ensartinib in lung adenocarcinoma but responded to lorlatinib: A case report

Targeting Gatekeeper Mutations for Kinase Drug Discovery

Anaplastic lymphoma kinase inhibitors—a review of anticancer properties, clinical efficacy, and resistance mechanisms

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