Reference Detail

Ref Type Journal Article
PMID (29132432)
Authors Lai YH, Lin SY, Wu YS, Chen HW, Chen JJW
Title AC-93253 iodide, a novel Src inhibitor, suppresses NSCLC progression by modulating multiple Src-related signaling pathways.
Journal Journal of hematology & oncology
Vol 10
Issue 1
Date 2017 Nov 13
URL
Abstract Text The tyrosine kinase Src is involved in the progression of many cancers. Moreover, inhibiting Src activity has been shown to obstruct several signaling pathways regulated by the EGFR. Thus, Src is a valuable target molecule in drug development. The purpose of this study was to identify compounds that directly or indirectly modulate Src to suppress lung cancer cell growth and motility and to investigate the molecular mechanisms underlying the effects of these compounds.Human non-small cell lung cancer (NSCLC) cell lines (PC9, PC9/gef, A549, and H1975) with different EGFR statuses were tested by cytotoxicity and proliferation assays after AC-93253 iodide treatment. Src and Src-related protein expression in AC-93253 iodide-treated PC9, PC9/gef, and A549 cells were assessed by western blotting. The effects of AC-93253 iodide on cancer cell colony formation, invasion, and migration were assessed in PC9 and PC9/gef cells. The synergistic effects of gefitinib and AC-93253 iodide were evaluated by combination index (CI)-isobologram analysis in gefitinib-resistant cell lines. The efficacy of AC-93253 iodide in vivo was determined using nude mice treated with either the compound or the vehicle.Among the compounds, AC-93253 iodide exhibited the most potent dose-independent inhibitory effects on the activity of Src as well as on that of the Src-related proteins EGFR, STAT3, and FAK. Furthermore, AC-93253 iodide significantly suppressed cancer cell proliferation, colony formation, invasion, and migration in vitro and tumor growth in vivo. AC-93253 iodide sensitized tumor cells to gefitinib treatment regardless of whether the cells were gefitinib-sensitive (PC9) or resistant (H1975 and PC9/gef), indicating that it may exert synergistic effects when used in combination with established therapeutic agents. Our findings also suggested that the inhibitory effects of AC-93253 iodide on lung cancer progression may be attributable to its ability to modulate multiple proteins, including Src, PI3K, JNK, Paxillin, p130cas, MEK, ERK, and EGFR.Our data suggest that AC-93253 iodide inhibits NSCLC cell growth and motility by regulating multiple Src-related pathways. Our findings may facilitate the development of therapeutic strategies and anti-tumor drugs that may be useful for treating lung cancer in the future.

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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
AC-93253 iodide AC-93253 iodide 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
AC-93253 iodide SRC Inhibitor 27 AC-93253 iodide is an inhibitor of SRC, which also results in reduced expression and phosphorylation of signaling molecules downstream of Src, potentially leading to decreased cell proliferation and inhibition of tumor growth (PMID: 29132432).
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
Unknown unknown lung adenocarcinoma predicted - sensitive AC-93253 iodide + Gefitinib Preclinical - Cell culture Actionable In a preclinical study, AC-93253 iodide combined with Iressa (gefitinib) resulted in a synergistic effect, demonstrating growth inhibition of an Iressa (gefitinib)-resistant lung adenocarcinoma cell line in culture (PMID: 29132432). 29132432
SRC positive lung non-small cell carcinoma predicted - sensitive AC-93253 iodide Preclinical - Cell line xenograft Actionable In a preclinical study, AC-93253 iodide reduced the expression and phosphorylation of Src in non-small cell lung carcinoma cells, which led to antitumor activity, including decreased cell proliferation, cell migration, cell invasion, and colony formation in culture and inhibition of tumor growth in cell line xenograft models (PMID: 29132432). 29132432