Inhibition of Src with AZD0530 Reveals the Src-Focal Adhesion Kinase Complex as a Novel Therapeutic Target in Papillary and Anaplastic Thyroid Cancer

Schweppe, Rebecca E.; Kerege, Anna A.; French, Jena D.; Sharma, Vibha; Grzywa, Rachel L.; Haugen, Bryan R.

doi:10.1210/jc.2008-2511

Cited by 55 publications

(63 citation statements)

References 24 publications

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“…Moreover, MSTO-211H, NCI-H28 and NCI-H2052 also showed an increase in the level of total SRC upon treatment suggesting the existence of a positive feedback loop that may try to compensate for SRC inhibition. This is consistent to what reported in various tumor cell lines following treatment with other SRC inhibitors (Shor et al, 2007;Schweppe et al, 2009).…”

Section: Resultssupporting

confidence: 92%

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

et al. 2011

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Malignant mesothelioma (MM) is a highly aggressive tumor of the serous membranes for which there is currently no effective curative modality. Recent data suggest that hyperactivation of the tyrosine kinase SRC has a key role in MM development and therefore this kinase represents an important molecular target for MM therapy. We tested new pyrazolo [3,4-d]pyrimidine SRC inhibitors on a panel of MM cell lines expressing the active form of SRC. These SRC inhibitors exerted a significant proapoptotic effect on MM cells without affecting the normal mesothelial cell line MET-5A, supporting a possible use of these SRC inhibitors for a safe treatment of MM. We also showed that SRC inhibitor-induced apoptosis occurred concomitantly with an increase in the nuclear stability of the cyclindependent kinase inhibitor p27. This finding is remarkable considering that loss of nuclear p27 expression is a wellestablished adverse prognostic factor in MM, and p27 nuclear localization is crucial for its tumor-suppressive function. Consistently, SRC inhibition seems to promote the increase in p27 nuclear level also by inactivating the AKT kinase and downregulating cyclin D1, which would otherwise delay p27 nuclear import and provoke its cytoplasmic accumulation. To determine whether p27 stabilization has a direct role in apoptosis induced by SRC inhibition, we stably silenced the CDKN1B gene, encoding p27, in MSTO-211H and REN mesothelioma cells by transduction with lentiviral vectors expressing short hairpin RNAs against the CDKN1B transcript. Strikingly, p27 silencing was able to suppress the apoptosis induced by these SRC inhibitors in both MM cell lines, suggesting that p27 has a crucial proapoptotic role in MM cells treated with SRC inhibitors. Our findings reveal a new mechanism, dependent on p27 nuclear stabilization, by which SRC inhibition can induce apoptosis in MM cells and provide a new rationale for the use of SRC inhibitors in MM therapy.

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Section: Resultssupporting

confidence: 92%

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

et al. 2011

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“…The role of the FAK pathway has recently been suggested to be important in PTC and ATC. Schweppe et al (14) characterized the antitumor effects of AZD0530, in PTC and ATC cells providing the first evidence that FAK is phosphorylated in a subset of PTC tumor samples (15,16). Our results showed that a different Tyrosine residue on FAK (Tyr 576/577) from that found in the study by Schweppe et al was phosphorylated in thyroid cancer (14).…”

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confidence: 53%

Effect of dasatinib against thyroid cancer cell lines in vitro and a xenograft model in vivo

et al. 2012

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Abstract. Tyrosine kinase inhibitors (TKIs) have emerged as a promising class of agents against thyroid cancer. The aim of the present study was to investigate the in vitro and in vivo activity of dasatinib against a panel of thyroid cancer cell lines and explore possible mechanisms of action, using various assays and western blotting. Our results showed that dasatinib exhibits prominent cytostatic activity both in vitro and in vivo against thyroid cancer cell lines with RET/PTC rearrangement (BHP2-7) and KRAS mutation (Cal62). Although dasatinib has primarily been described as an ABL/SRCfamily kinase inhibitor, the cytostatic activity observed in the present study is mediated by several off-target effects of dasatinib, some of which have not previously been reported. These effects include a reduction in phospho-FAK, FAK, RAS, Caveolin and SYK protein levels and an increase in β-catenin protein expression, which leads to the induction of senescence, an increase in the adhesiveness of the cells, a decrease in reactive oxygen species level, and changes in the expression profile of molecules involved in cellular adhesion such as integrins. Therefore, we propose that dasatinib is an effective therapeutic agent for certain patients with thyroid cancer, and these candidate patients may be identifiable on the basis of standard genotypic analyses.

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“…Preclinical studies on papillary and anaplastic thyroid cancer cell lines showed no correlation between p-Src levels and response to saracatinib, but high levels of p-FAK were strongly correlated with saracatinib sensitivity. These data suggest that p-FAK may be a better predictive biomarker in thyroid cancer than p-Src [91]. In the clinical arena, biomarkers established in preclinical work are currently being measured in pre-and post-treatment samples to determine whether high expression in pretreatment patients predicts response and whether that response is correlated with a corresponding decrease in biomarker levels.…”

Section: Biomarkers In Src-targeted Therapiesmentioning

confidence: 99%

Current Status of Src Inhibitors in Solid Tumor Malignancies

2011

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Summary. Src is believed to play an important role in cancer, and several agents targeting Src are in clinical development.Design. We reviewed Src structure and function and preclinical data supporting its role in the development of cancer via a PubMed search. We conducted an extensive review of Src inhibitors by searching abstracts from major oncology meeting databases in the last 3 years and by comprehensively reviewing ongoing clinical trials on ClinicalTrials.gov.Results. In this manuscript, we briefly review Src structure and function, mechanisms involving Src that lead to the development of cancer, and Src inhibitors and key preclinical data establishing a rationale for clinical application. We then focus on clinical data supporting their use in solid tumor malignancies, a newer arena than their more well-established hematologic applications. Particularly highlighted are clinical trials investigating new biomarkers as well as ongoing studies assessing Src inhibitor activity in biomarker-selected patient populations. We also review newer investigational Src-targeting agents.Conclusions. Src inhibitors have shown little activity in monotherapy trials in unselected solid tumor patient populations. Combination studies and biomarker-driven clinical trials are under way. The Oncologist 2011;16:566 -578

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Inhibition of Src with AZD0530 Reveals the Src-Focal Adhesion Kinase Complex as a Novel Therapeutic Target in Papillary and Anaplastic Thyroid Cancer

Abstract: Inhibition of the Src-FAK complex represents a promising therapeutic strategy for patients with advanced thyroid cancer, and phospho-FAK represents a potential biomarker for response.

Cited by 55 publications

References 24 publications

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

Effect of dasatinib against thyroid cancer cell lines in vitro and a xenograft model in vivo

Current Status of Src Inhibitors in Solid Tumor Malignancies

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