Reference Detail

Ref Type

Journal Article

PMID

(36681369)

Authors

Lei T, Xu T, Zhang N, Zou X, Kong Z, Wei C, Wang Z

Title

Anlotinib combined with osimertinib reverses acquired osimertinib resistance in NSCLC by targeting the c-MET/MYC/AXL axis.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Pharmacological research	188		2023 Feb	106668	Pharmacol Res

URL

Abstract Text

Favorable clinical evidence suggests that the next trend in new treatments for advanced non-small cell lung cancer (NSCLC) will be combination therapies. However, inevitable epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance greatly limits the clinical efficacy of patients carrying EGFR-activating mutants. In this study, we found a patient with clinical osimertinib resistance who regained a positive response after osimertinib plus anlotinib treatment. Two osimertinib-resistant cell lines were constructed, and AXL conferred resistance to osimertinib in NSCLC cell lines. The combined effects of anlotinib and osimertinib restored sensitivity to osimertinib in two osimertinib-resistant NSCLC cell lines and in xenografts. Moreover, anlotinib inhibits the phosphorylation of AXL in both resistant cell lines. Mechanistically, we confirmed that MYC binds to the promoter of AXL to promote its transcription in NSCLC cells, and we demonstrated that anlotinib combined with osimertinib treatment enhances the anti-tumor effect by inactivating the c-MET/MYC/AXL axis to reverse osimertinib resistance in NSCLC. In conclusion, our results provide strong support that this combination therapy may be effective in enhancing the efficacy of treatments in patients with advanced NSCLC.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
AXL over exp	lung non-small cell carcinoma	sensitive	Anlotinib + Osimertinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Anlotinib (AL-3818) and Tagrisso (osimertinib) inhibited proliferation and viability in Tagrisso (osimertinib)-resistant non-small cell lung cancer cell lines with overexpression of AXL in culture, and inhibited tumor growth in cell line xenograft models (PMID: 36681369).	36681369
AXL over exp	lung non-small cell carcinoma	resistant	Osimertinib	Preclinical - Cell culture	Actionable	In a preclinical study, non-small cell lung cancer cell lines overexpressing AXL were resistant to treatment with Tagrisso (osimertinib) in culture (PMID: 36681369).	36681369