Reference Detail

Ref Type

Journal Article

PMID

(35085771)

Authors

Shen J, Meng Y, Wang K, Gao M, Du J, Wang J, Li Z, Zuo D, Wu Y

Title

EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cellular signalling	92		2022 04	110264	Cell Signal

URL

Abstract Text

The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene occurs in approximately 5% of non-small-cell lung cancers (NSCLCs). The development of ALK tyrosine kinase inhibitors (ALK-TKIs) is a major advance in treating NSCLC with the ALK fusion gene. Nevertheless, acquired resistance to ALK-TKIs ultimately limits their use. A prevalent mechanism of drug resistance in kinases occurs through the mutation of G1202R in ALK. However, the mechanisms underlying G1202R resistance to ceritinib are not fully understood. Here, we demonstrated that the expression of EML4-ALK G1202R mutation in A549 cells induced an epithelial-mesenchymal transition (EMT) phenotype and significantly increased the migration and invasion abilities. These phenomena may be due to the upregulation of signal transducer and activator of transcription 3 (STAT3), accompanied by the elevated expression of Slug in EML4-ALK G1202R mutant cells. Furthermore, the combination of ALK and STAT3 inhibitors restored the sensitivity of EML4-ALK G1202R mutant cells to ceritinib. In conclusion, these data indicate that the EML4-ALK G1202R mutation mediates the EMT phenotype by activating the STAT3/Slug signaling pathway, resulting in resistance to ceritinib, and that the combination of STAT3 and ALK inhibitors may overcome ALK mutation-driven drug resistance in the clinic.

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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
HJC0152	HJC0152	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
HJC0152		HJC-0152\|HJC 0152	STAT3 Inhibitor 26	HJC0152 inhibits STAT3, potentially leading to induction of apoptosis and decreased proliferation, migration, invasion, and tumor growth (PMID: 30588091, PMID: 35085771).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
ALK	G1202R	missense	unknown	ALK G1202R lies within the protein kinase domain of the Alk protein (UniProt.org). G1202R demonstrates increased colony formation, decreased Cdh1 expression, increased migration and invasion, increased expression of metastatic factors Cdh2, Vim, Mmp2, Mmp9, and Slug in cell culture in the context of EML4-ALK (PMID: 35085771), and drug resistance in the context of ALK fusions (PMID: 22277784, PMID: 24736079, PMID: 35085771), but has not been individually characterized and therefore, its effect on Alk protein function is unknown.	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK G1202R	lung non-small cell carcinoma	sensitive	HJC0152	Preclinical - Cell culture	Actionable	In a preclinical study, HJC0152 treatment decreased Stat signaling, migration, and invasion in a non-small cell lung cancer cell line expressing EML4-ALK and ALK G1202R in culture (PMID: 35085771).	35085771
EML4 - ALK ALK G1202R	lung non-small cell carcinoma	sensitive	Ceritinib + HJC0152	Preclinical - Cell culture	Actionable	In a preclinical study, HJC0152 and Zykadia (ceritinib) combination treatment increased apoptosis and decreased viability and colony formation in a non-small cell lung cancer cell line expressing EML4-ALK and ALK G1202R compared to either drug alone in culture (PMID: 35085771).	35085771