Impact of STAT3 Phosphorylation on the Clinical Effectiveness of Anti-EGFR–Based Therapy in Patients With Metastatic Colorectal Cancer

Dobi, Erion; Monnien, Franck; Kim, Stéfano; Ivanaj, Arben; N'Guyen, Thiery; Demarchi, Martin; Adotévi, Olivier; Thierry-Vuillemin, Antoine; Jary, M.; Kantélip, B.; Pivot, Xavier; Godet, Yann; Degano, Séverine Valmary; Borg, Christophe

doi:10.1016/j.clcc.2012.09.002

Cited by 38 publications

(42 citation statements)

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“…However, a previous comprehensive study by Morikawa and colleagues found no association between STAT3, a number of molecular characteristics and survival in a cohort of over 700 patients (33). Furthermore, it has also been suggested that STAT3 may have a role in not only induction of KRAS mutated tumours (53), but also in conferring chemoresistance in patients with KRAS wild-type tumours (54). Indeed, this would suggest that STAT3 is independent of such characteristics.…”

Section: P=0039)mentioning

confidence: 96%

Signal Transduction and Activator of Transcription-3 (STAT3) in Patients with Colorectal Cancer: Associations with the Phenotypic Features of the Tumor and Host

Park

Wyk

McMillan

et al. 2017

Clinical Cancer Research

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(2017) Signal transduction and activator of transcription-3 (STAT3) in patients with colorectal cancer: associations with the phenotypic features of the tumour and host. Clinical Cancer Research, 23(7), pp. 1698 -1709 . (doi:10.1158 /1078 -0432.CCR-16-1416 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/129347/ Experimental DesignImmunohistochemical assessment of STAT3/pSTAT3 expression was performed using a tissue microarray and tumour cell expression divided into tertiles using the weighted histoscore. The relationship between STAT3/pSTAT3 expression and local inflammatory The combination of nuclear STAT3/pSTAT3 stratified five-year survival from 81% to 62% (P=0.012), however was not associated with survival independent of venous invasion, tumour perforation or tumour budding. ConclusionIn patients undergoing CRC resection, STAT3 expression was associated with adverse host inflammatory responses and reduced survival. Up-regulation of tumour STAT3 may be an important mechanism whereby the tumour deregulates local and systemic inflammatory responses.5

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Section: P=0039)mentioning

confidence: 96%

Signal Transduction and Activator of Transcription-3 (STAT3) in Patients with Colorectal Cancer: Associations with the Phenotypic Features of the Tumor and Host

Park

Wyk

McMillan

et al. 2017

Clinical Cancer Research

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“…The inhibition of Bcl-2 and Bcl-xl expression and the increase in Bax protein level, thus, provide a mechanistic basis of apoptosis induction by TQ. The expression of anti-apoptotic proteins Bcl-2 and Bcl-xl is transcriptionally regulated by STAT3 (25), which is overexpressed in colon cancer (24,37). Persistent STAT3 activation increases the proliferation of colon cancer cells in culture and enhances the growth of colon cancer cell xenograft tumors in nude mice (38).…”

Section: Discussionmentioning

confidence: 99%

Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2- and Src-mediated phosphorylation of EGF receptor tyrosine kinase

et al. 2014

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Abstract. Thymoquinone (TQ), a compound isolated from black seed oil (Nigella sativa), has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of TQ remain poorly understood. In the present study, we found that TQ significantly reduced the viability of human colon cancer HCT116 cells in a concentration-and time-dependent manner. Treatment of cells with TQ induced apoptosis, which was associated with the upregulation of Bax and inhibition of Bcl-2 and Bcl-xl expression. TQ also activated caspase-9,-7, and -3, and induced the cleavage of poly-(ADP-ribose) polymerase (PARP). Pretreatment with a pan-caspase inhibitor, z-VAD-fmk, abrogated TQ-induced apoptosis by blocking the cleavage of caspase-3 and PARP. Treatment of cells with TQ also diminished the constitutive phosphorylation, nuclear localization and the reporter gene activity of signal transducer and activator of transcription-3 (STAT3). TQ attenuated the expression of STAT3 target gene products, such as survivin, c-Myc, and cyclin-D1, -D2, and enhanced the expression of cell cycle inhibitory proteins p27 and p21. Treatment with TQ attenuated the phosphorylation of upstream kinases, such as Janus-activated kinase-2 (JAK2), Src kinase and epidermal growth factor receptor (EGFR) tyrosine kinase. Pharmacological inhibition of JAK2 and Src blunted tyrosine phosphorylation of EGFR and STAT3, while treatment with an EGFR tyrosine kinase inhibitor gefitinib inhibited phosphorylation of STAT3 without affecting that of JAK2 and Src in HCT116 cells. Collectively, our study revealed that TQ induced apoptosis in HCT116 cells by blocking STAT3 signaling via inhibition of JAK2-and Src-mediated phosphorylation of EGFR tyrosine kinase. IntroductionColorectal cancer is one of the leading causes of mortality and ranks among the three most common cancers in developed countries (1,2). More than one million new cases of colorectal cancer are diagnosed every year (3). Multiple lines of evidence suggest that bioactive compounds present in various edible and medicinal plants can prevent colon carcinogenesis (4). Thymoquinone (TQ; Fig. 1A), a dietary phytochemical, is the major bioactive constituent present in black seed oil (Nigella sativa), which is widely consumed as a condiment and has long been used in Ayurvedic medicine. TQ has been reported to exert antioxidative, anti-inflammatory and anticancer effects (5-7). Several studies have reported that TQ inhibits cell proliferation, induces apoptosis and impedes the in vivo growth of xenograft tumors of various human cancer cells including those of the stomach (8,9), colorectal (10,11), lungs (12), breast (5) and prostate (13). In a recent study, TQ was shown to inhibit 1,2-dimethylhydrazine-induced initiation and promotion of colon carcinogenesis in Wister rats (14). However, the molecular basis of the anticancer effects of TQ in colon cancer has yet to be fully elucidated.Evasion from apoptosis is one of the hallmarks of cancer (15). Tumor cells ...

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“…38,40,41 Importantly, STAT3 activation was recently identified as a potential predictive marker for resistance to anti-EGFR therapies in patients with mCRC and NSCLC. 42,43 Inhibiting STAT3 in combination with anti-EGFR therapeutics have also revealed promising data pre-clinically, emphasizing the potential benefit of targeting of STAT3 to optimize anti-EGFR therapy in the clinic. [44][45][46][47] Our present study utilizes a STAT3 transcriptional reporter to demonstrate that efficacy of anti-EGFR therapeutics correlates with their ability to inhibit STAT3 activation in culture and in animal xenograft studies.…”

Section: Introductionmentioning

confidence: 97%

Anti-EGFR therapeutic efficacy correlates directly with inhibition of STAT3 activity

Ung

Putoczki

Stylli

et al. 2014

Cancer Biology & Therapy

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Several agents targeting the epidermal growth factor receptor (EGFR) have been FDA-approved to treat cancer patients with varying tumor types including metastatic colorectal cancer. Many patients treated with anti-EGFR therapy however do not respond and those that do initially respond often acquire resistance. Here we show a clear correlation between the efficacy of anti-EGFR inhibitors with their ability to inhibit STAT3 activity in A431 epidermoid carcinoma cells and in a series of wt K-RAS expressing human colon cancer cell lines. Furthermore, the ability of cetuximab to inhibit growth also correlated with its ability to inhibit STAT3 activity in tumor xenograft animal studies. In addition, stable knockdown of the STAT3 phosphatase, protein tyrosine phosphatase receptor delta (PTPRD) resulted in enhanced STAT3 activity and subsequent resistance to cetuximab in DIFI colon carcinoma cells. This resistance could be reversed by STAT3 inhibition. Finally, HN5 cells with acquired resistance to the EGFR tyrosine kinase inhibitor, AG1478 displayed greater STAT3 activity than the HN5 control cell line. These AG1478-refractory HN5 cells were re-sensitized to AG1478, cetuximab and erlotinib when co-treated with a STAT3 inhibitor. Taken together, our current data indicates a key role of STAT3 activity in promoting resistance to anti-EGFR therapy and suggests that anti-EGFR therapy in combination with inhibitors that block STAT3 may provide therapeutic benefit for patients with mCRC and other EGFR driven tumor types.

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Impact of STAT3 Phosphorylation on the Clinical Effectiveness of Anti-EGFR–Based Therapy in Patients With Metastatic Colorectal Cancer

Abstract: These results underscore an impact of pSTAT3 on the clinical efficacy of anti-EGFR-containing chemotherapy regimens and support the prospective assessment of this biomarker.

Cited by 38 publications

References 35 publications

Signal Transduction and Activator of Transcription-3 (STAT3) in Patients with Colorectal Cancer: Associations with the Phenotypic Features of the Tumor and Host

Signal Transduction and Activator of Transcription-3 (STAT3) in Patients with Colorectal Cancer: Associations with the Phenotypic Features of the Tumor and Host

Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2- and Src-mediated phosphorylation of EGF receptor tyrosine kinase

Anti-EGFR therapeutic efficacy correlates directly with inhibition of STAT3 activity

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