SKI-606 (Bosutinib) Blocks Prostate Cancer Invasion, Growth, and Metastasis <i>In vitro</i> and <i>In vivo</i> through Regulation of Genes Involved in Cancer Growth and Skeletal Metastasis

Rabbani, Shafaat A.; Valentino, Maria-Luisa; Arakelian, Ani; Ali, Suhad; Boschelli, Frank

doi:10.1158/1535-7163.mct-09-0962

Cited by 55 publications

(42 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, bosutinib monotherapy demonstrated potent antimigratory and anti-invasive activity against BTC cell lines, and downregulated the expression of proteins related to EMT, which is associated with cancer progression and metastasis and often mediated by the MAPK and PI3K/AKT pathways (35,36). These findings are also consistent with previous findings of bosutinib in other type of cancers (29,30,37,38). The results of our preclinical studies support bosutinib as a single agent with promising antitumor activity in BTC, which warrants further clinical studies.…”

Section: Discussionsupporting

confidence: 90%

Src as a Therapeutic Target in Biliary Tract Cancer

Nam

Kim

Park

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Src, a nonreceptor tyrosine kinase, is involved in a number of cancer-related signaling pathways and aberrantly activated in biliary tract cancer (BTC). This study aimed to elucidate the potential role of Src as a therapeutic target in BTC. We tested bosutinib, an orally active c-Src/Abl kinase inhibitor, alone or in combination with cytotoxic agents using 9 human BTC cell lines: SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079, SNU-1196, HuCCT1, TFK-1, and EGI-1. Of these, SNU-308 and SNU-478 were relatively sensitive to bosutinib. Bosutinib abrogated phosphorylation of Src and its downstream molecules, and significantly increased G 1 cell-cycle arrest and apoptosis. Bosutinib significantly inhibited cell migration and invasion and decreased epithelial-mesenchymal transition markers. Bosutinib combined with gemcitabine or cisplatin showed synergistic antiproliferative and antimigratory effects.In addition, this combination further inhibited phosphorylation of Src and its downstream molecules and decreased epithelial-mesenchymal transition marker expression compared with bosutinib alone. We established a SNU-478 xenograft model for in vivo experiments, because SNU-478 was more tumorigenic than SNU-308. Bosutinib combined with gemcitabine or cisplatin showed significantly more potent antitumor effects than bosutinib alone. Bosutinib combined with gemcitabine further decreased Ki-67 expression and Src phosphorylation, and further increased TUNEL expression. Our data suggest that Src might be a potential therapeutic target in BTC. Bosutinib demonstrated promising antitumor activity alone or in combination with gemcitabine or cisplatin in BTC cells, which supports further clinical development in patients with advanced BTC. Mol Cancer Ther; 15(7); 1515-24. Ó2016 AACR.

show abstract

Section: Discussionsupporting

confidence: 90%

Src as a Therapeutic Target in Biliary Tract Cancer

Nam

Kim

Park

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…120 Inhibition of SFKs and c-Abl/Arg with bosutinib blocked migration, invasion, anchorage-independent growth, and proliferation of PC3 and DU-145 prostate cancer cells, which was accompanied by decreased Akt, ERK1/2, and FAK phosphorylation. 121 Furthermore, bosutinib inhibited PC-3 tumor growth initiated by subcutaneous or intraskeletal injection. 121 Silencing Src produced similar effects as bosutinib; however, the authors did not investigate whether the effects also could be mediated by Src-dependent activation of c-Abl/Arg and/or due to direct inhibition of c-Abl/Arg by bosutinib.…”

Section: Prostate Cancermentioning

confidence: 98%

“…121 Furthermore, bosutinib inhibited PC-3 tumor growth initiated by subcutaneous or intraskeletal injection. 121 Silencing Src produced similar effects as bosutinib; however, the authors did not investigate whether the effects also could be mediated by Src-dependent activation of c-Abl/Arg and/or due to direct inhibition of c-Abl/Arg by bosutinib. Bone metastases, which are common for prostate and breast cancers, increase morbidity and mortality.…”

Section: Prostate Cancermentioning

confidence: 98%

Activation of Abl Family Kinases in Solid Tumors

Ganguly

Plattner

2012

Genes & Cancer

View full text Add to dashboard Cite

Although c-Abl and Arg non-receptor tyrosine kinases are well known for driving leukemia development, their role in solid tumors has not been appreciated until recently. Accumulating evidence now indicates that c-Abl and/or Arg are activated in some solid tumor cell lines via unique mechanisms that do not involve gene mutation/translocation, and c-Abl/Arg activation promotes matrix degradation, invasion, proliferation, tumorigenesis, and/ or metastasis, depending on the tumor type. However, some data suggest that c-Abl also may suppress invasion, proliferation, and tumorigenesis in certain cell contexts. Thus, c-Abl/Arg may serve as molecular switches that suppress proliferation and invasion in response to some stimuli (e.g., ephrins) or when inactive/regulated, or as promote invasion and proliferation in response to other signals (e.g., activated growth factor receptors, loss of inhibitor expression), which induce sustained activation. Clearly, more data are required to determine the extent and prevalence of c-Abl/Arg activation in primary tumors and during progression, and additional animal studies are needed to substantiate in vitro findings. Furthermore, c-Abl/ Arg inhibitors have been used in numerous solid tumor clinical trials; however, none of these trials were restricted to patients whose tumors expressed highly activated c-Abl/Arg (targeted trial). Targeted trials are critical for determining whether c-Abl/Arg inhibitors can be effective treatment options for patients whose tumors are driven by c-Abl/Arg.

show abstract

“…In addition to inhibiting Src family kinases, bosutinib also inhibits EGFR (including L858R and L861Q), EphB2, and members of the Sterile 20, Tec, and c-Kit kinase families in vitro (7). Bosutinib inhibits solid tumors such as pancreas (8), breast (9,10), prostate (9), and melanoma (11) in preclinical models. It is also being developed for the treatment of chronic myelogenous leukemia (CML) via Abl inhibition (12)(13)(14)(15), as most agents in this class inhibit both Src and Abl.…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors

Daud

Krishnamurthi

Saleh

et al. 2012

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies.Patients and Methods: This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 þ 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non-small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non-small cell lung) and median overall survival (pancreas).Results: In part 1, dose-limiting toxicities of grade 3 diarrhea (two patients) and grade 3 rash occurred with bosutinib 600 mg/day and the maximum tolerated dose identified was 500 mg/day. However, the majority of patients treated with 500 mg/day had grade 2 or greater gastrointestinal toxicity, and 400 mg/day was identified as the RP2D. The most common bosutinib-related adverse events were nausea (60% patients), diarrhea (47%), vomiting (40%), fatigue (38%), and anorexia (36%). Bosutinib had a mean half-life of 19 to 20 hours at the RP2D. A partial response (breast) and unconfirmed complete response (pancreas) were observed; 8 of 112 evaluable patients had stable disease for 22 to 101 weeks. However, the primary efficacy endpoints for part 2 were not met.Conclusions: Bosutinib was generally well tolerated in patients with solid tumors, with the main toxicity being gastrointestinal. The RP2D was 400 mg/day orally. Further study of bosutinib is planned in combination regimens.

show abstract

SKI-606 (Bosutinib) Blocks Prostate Cancer Invasion, Growth, and Metastasis In vitro and In vivo through Regulation of Genes Involved in Cancer Growth and Skeletal Metastasis

Cited by 55 publications

References 43 publications

Src as a Therapeutic Target in Biliary Tract Cancer

Src as a Therapeutic Target in Biliary Tract Cancer

Activation of Abl Family Kinases in Solid Tumors

Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors

Contact Info

Product

Resources

About