Reference Detail

Ref Type

Journal Article

PMID

(24100628)

Authors

Liu T, Hu W, Dalton HJ, Choi HJ, Huang J, Kang Y, Pradeep S, Miyake T, Song JH, Wen Y, Lu C, Pecot CV, Bottsford-Miller J, Zand B, Jennings NB, Ivan C, Gallick GE, Baggerly KA, Hangauer DG, Coleman RL, Frumovitz M, Sood AK

Title

Targeting SRC and tubulin in mucinous ovarian carcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	19	23	2013 Dec 01	6532-43	Clin Cancer Res

URL

Abstract Text

To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma.The in vitro and in vivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models.In vitro studies using RMUG-S and RMUG-L cell lines showed that KX-01 inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G2-M phase, and enhanced the cytotoxicity of oxaliplatin in the KX-01-sensitive cell line, RMUG-S. In vivo studies showed that KX-01 significantly decreased tumor burden in RMUG-S and RMUG-L mouse models relative to untreated controls, and the effects were greater when KX-01 was combined with oxaliplatin. KX-01 alone and in combination with oxaliplatin significantly inhibited tumor growth by reducing cell proliferation and inducing apoptosis in vivo. PTEN knock-in experiments in RMUG-L cells showed improved response to KX-01. Reverse phase protein array analysis showed that in addition to blocking downstream molecules of Src family kinases, KX-01 also activated acute stress-inducing molecules.Our results showed that targeting both the Src pathway and tubulin with KX-01 significantly inhibited tumor growth in preclinical mucinous ovarian cancer models, suggesting that this may be a promising therapeutic approach for patients with mucinous ovarian carcinoma.

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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
PTEN wild-type	ovarian mucinous neoplasm	sensitive	KX2-391 + Oxaliplatin	Preclinical	Actionable	In a preclinical study, KX2-391 and Eloxatin (oxaliplatin) synergistically inhibited survival of PTEN wild-type mucinous ovarian carcinoma cell lines in culture, and reduced tumor growth in xenograft models (PMID: 24100628).	24100628
PTEN wild-type	ovarian mucinous neoplasm	sensitive	KX2-391	Preclinical	Actionable	In a preclinical study, KX2-391 inhibited survival of PTEN wild-type mucinous ovarian carcinoma cell lines in culture, and reduced tumor growth in xenograft models (PMID: 24100628).	24100628
PTEN loss	ovarian mucinous neoplasm	no benefit	KX2-391 + Oxaliplatin	Preclinical	Actionable	In a preclinical study, KX2-391 and Eloxatin (oxaliplatin) combination treatment did not show improved tumor suppression in xenograft models of ovarian mucinous carcinoma harboring PTEN loss when compared to single agent treatment (PMID: 24100628).	24100628
PTEN loss	ovarian mucinous neoplasm	decreased response	KX2-391	Preclinical	Actionable	In a preclincal study, mucinous ovarian carcinoma cell lines harboring PTEN loss were less sensitive to KX2-391 induced growth inhibition in culture and tumor suppression in xenograft models (PMID: 24100628).	24100628
PTEN G129R	ovarian mucinous neoplasm	decreased response	KX2-391	Preclinical	Actionable	In a preclincal study, mucinous ovarian carcinoma cell lines over-expressing PTEN G129R were less sensitive to KX2-391 induced growth inhibition in culture and tumor suppression in xenograft models (PMID: 24100628).	24100628