Therapeutic targeting of Trk supresses tumor proliferation and enhances cisplatin activity in HNSCC

Yilmaz, Türker; Jiffar, Tilahun; Garza, Gabriel; Lin, Heather; Milas, Zvonimir L.; Takahashi, Yoko; Hanna, Ehab Y.; Macintyre, Terry; Brown, Jeffrey L.; Myers, Jeffrey N.; Kupferman, Michael E.

doi:10.4161/cbt.10.6.12782

Cited by 34 publications

(54 citation statements)

References 27 publications

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“…The characteristics of these cells have been reported previously (Yilmaz et al ., 2010). We next utilized a mouse model of HNSCC to assess the in vivo biological behavior of the CDDP-resistant (CR) cells, and observed a profound enhancement of both local tumor growth (Figure 1a), lymphatic and distant metastasis in the CR cells, compared with the parental cells (Figure 1b).…”

Section: Resultssupporting

confidence: 68%

KiSS1 mediates platinum sensitivity and metastasis suppression in head and neck squamous cell carcinoma

Jiffar¹,

Yilmaz²,

Lee³

et al. 2011

Oncogene

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Although surgery and radiotherapy have been the standard treatment modalities for head and neck squamous cell carcinoma (HNSCC), the integration of cisplatin (CDDP)-based therapy has led to improvements in local and regional control of disease for patients. However, many trials show that only 10–20% of patients benefit from this treatment intensification, which can result in profound treatment-associated morbidity and mortality. Moreover, the marginal survival improvement suggests that CDDP resistance is an innate characteristic of HNSCC. To elucidate the biological mechanisms underpinning CDDP resistance in HNSCC, we utilized an experimental model of CDDP resistance in this disease. We first observed significant enhancements in local tumor growth and metastasis, as well as adverse survival, in CDDP-resistant (CR) tumors compared with sensitive tumors. To elucidate the molecular mechanisms of this phenotype, we undertook a systems biology-based approach utilizing high-throughput PCR arrays, and we identified a significant suppression of KiSS1 mRNA and protein expression in the CR cells, but no significant regions of genomic loss with array comparative genomic hybridization. Genetic suppression of KiSS1 in CDDP-sensitive cell lines rendered them CR, an observation that was mechanistically linked to alterations in glutathione S-transferase-π expression and function. We next confirmed that, in human HNSCC tumors, loss of KiSS1 expression was associated with metastatic human HNSCC tumors compared with non-metastatic tumors. Genetic reconstitution of KiSS1 in CR cells abrogated cellular migration and induced CDDP sensitivity. To confirm these findings in a murine model, either CR or KiSS1-transfected CR cells were studied in an orthotopic model of HNSCC, or survival studies revealed significant improvement in survival of the mice bearing CR-KiSS1 tumors. Mechanistically, alterations in apoptotic pathways and CDDP metabolism contributed to KiSS1-associated chemotherapy sensitization. These studies provided further direct evidence for the role of KiSS1 loss in biologically aggressive HNSCC and suggest potential targets for therapy in CR cancers.

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Section: Resultssupporting

confidence: 68%

KiSS1 mediates platinum sensitivity and metastasis suppression in head and neck squamous cell carcinoma

Jiffar¹,

Yilmaz²,

Lee³

et al. 2011

Oncogene

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“…Some reports have shown that the inhibition of STAT3 could sensitize tumor cells to cisplatin-induced cell death [Sims et al, 2009;Liu et al, 2010;Yilmaz et al, 2010]. Therefore, we postulate that arctigenin may promote chemosensitivity of tumor cells to cisplatin through inhibition of STAT3 activity.…”

Section: Discussionmentioning

confidence: 88%

Arctigenin enhances chemosensitivity of cancer cells to cisplatin through inhibition of the STAT3 signaling pathway

et al. 2011

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Arctigenin is a dibenzylbutyrolactone lignan isolated from Bardanae fructus, Arctium lappa L, Saussureamedusa, Torreya nucifera, and Ipomea cairica. It has been reported to exhibit anti-inflammatory activities, which is mainly mediated through its inhibitory effect on nuclear transcription factor-kappaB (NF-κB). But the role of arctigenin in JAK-STAT3 signaling pathways is still unclear. In present study, we investigated the effect of arctigenin on signal transducer and activator of transcription 3 (STAT3) pathway and evaluated whether suppression of STAT3 activity by arctigenin could sensitize cancer cells to a chemotherapeutic drug cisplatin. Our results show that arctigenin significantly suppressed both constitutively activated and IL-6-induced STAT3 phosphorylation and subsequent nuclear translocation in cancer cells. Inhibition of STAT3 tyrosine phosphorylation was found to be achieved through suppression of Src, JAK1, and JAK2, while suppression of STAT3 serine phosphorylation was mediated by inhibition of ERK activation. Pervanadate reversed the arctigenin-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, arctigenin can obviously induce the expression of the PTP SHP-2. Furthermore, the constitutive activation level of STAT3 was found to be correlated to the resistance of cancer cells to cisplatin-induced apoptosis. Arctigenin dramatically promoted cisplatin-induced cell death in cancer cells, indicating that arctigenin enhanced the sensitivity of cancer cells to cisplatin mainly via STAT3 suppression. These observations suggest a novel anticancer function of arctigenin and a potential therapeutic strategy of using arctigenin in combination with chemotherapeutic agents for cancer treatment.

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“…This compound inhibits Trk family kinases at nanomolar concentrations, and AZ64 can be administered orally, which makes it appealing for clinical treatment. Another group has tested AZ64 in head and neck models [65]. Also, a related compound, AZ-23/AZ623, was found to inhibit neuroblastoma growth and was synergistic with topotecan [61, 66], but it was not being developed for clinical trials.…”

Section: Discussionmentioning

confidence: 99%

AZ64 inhibits TrkB and enhances the efficacy of chemotherapy and local radiation in neuroblastoma xenografts

Iyer

Varela

Minturn

et al. 2012

Cancer Chemother Pharmacol

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Neuroblastoma is a common pediatric tumor characterized by clinical heterogeneity. Because it is derived from sympathetic neuroblasts, the NTRK family of neurotrophin receptors plays an integral role in neuroblastoma cell survival, growth, and differentiation. Indeed, high expression of NTRK1 is associated with favorable clinical features and outcome, whereas expression of NTRK2 and its ligand, brain-derived neurotrophic factor (BDNF), are associated with unfavorable features and outcome. AZ64 (Astra Zeneca) is a potent and selective inhibitor of the NTRK tyrosine kinases that blocks phosphorylation at nanomolar concentrations. To determine the preclinical activity of AZ64, we performed intervention trials in a xenograft model with NTRK2-overexpressing neuroblastomas. AZ64 alone significantly inhibited tumor growth compared to vehicle-treated animals (p = 0.0006 for tumor size). Furthermore, the combination of AZ64 with conventional chemotherapeutic agents, irinotecan and temozolomide (irino–temo), showed significantly enhanced anti-tumor efficacy compared to irino–temo alone [(p < 0.0001 for tumor size, p < 0.0005 for event-free survival (EFS)]. We also assessed the combination of AZ64 and local radiation therapy (RT) on a neuroblastoma hindlimb xenograft model, and the efficacy of local RT was significantly increased when animals were treated simultaneously with AZ64 (p < 0.0001 for tumor size, p = 0.0006 for EFS). We conclude that AZ64 can inhibit growth of NTRK-expressing neuroblastomas both in vitro and in vivo. More importantly, it can significantly enhance the efficacy of conventional chemotherapy as well as local RT, presumably by inhibition of the NTRK2/BDNF autocrine survival pathway.

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Therapeutic targeting of Trk supresses tumor proliferation and enhances cisplatin activity in HNSCC

Cited by 34 publications

References 27 publications

KiSS1 mediates platinum sensitivity and metastasis suppression in head and neck squamous cell carcinoma

KiSS1 mediates platinum sensitivity and metastasis suppression in head and neck squamous cell carcinoma

Arctigenin enhances chemosensitivity of cancer cells to cisplatin through inhibition of the STAT3 signaling pathway

AZ64 inhibits TrkB and enhances the efficacy of chemotherapy and local radiation in neuroblastoma xenografts

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