Emerging Roles of Targeted Small Molecule Protein-Tyrosine Kinase Inhibitors in Cancer Therapy

Smith, John K.; Mamoon, Naila M.; Duhé, Roy J.

doi:10.3727/000000003772462298

Cited by 87 publications

(44 citation statements)

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“…In general, cMet pathway can be activated through: i) paracrine or autocrine HGF, ii) amplification of c-Met gene locus, and iii) activating mutations in the kinase domain of the c-Met receptor (37,38). Of note, our data in the present study suggest that c-Met is activated through binding of HGF, as none of the cell lines exhibited a notable response to different concentrations of cMet inhibitor in vitro or in vivo.…”

Section: Discussionmentioning

confidence: 53%

“…Here, we investigated modes of resistance to sunitinib, which is clinically approved for metastatic renal cell carcinoma and imatinib-resistant or intolerant gastrointestinal stromal tumor and is in several trials for other tumor types including lung cancers (37,38). Sunitinib efficacy in murine lines in the current study, and in comparison with recent reports (23,24), indicates that blocking the receptor-mediated signaling is as efficacious as blocking the ligand in inhibiting tumor growth.…”

Section: Discussionmentioning

confidence: 84%

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HGF/c-Met Acts as an Alternative Angiogenic Pathway in Sunitinib-Resistant Tumors

et al. 2010

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Molecular and cellular mechanisms underlying resistance/low responsiveness to antiangiogenic compounds are under extensive investigations. Both populations of tumor and stroma (nontumor compartment) seem to contribute in inherent/acquired resistance to antiangiogenic therapy. Here, investigating in vivo efficacy of sunitinib in experimental models resulted in the identification of tumors that were resistant/ sensitive to the therapy. Analysis of tumor protein lysates indicated a greater concentration of hepatocyte growth factor (HGF) in resistant tumors than in sensitive ones. In addition, using flow cytometry, c-Met expression was found to be significantly higher in endothelial cells than in tumor cells, suggesting that HGF might target the vascular endothelial cells in resistant tumors. Combination of sunitinib and a selective c-Met inhibitor significantly inhibited tumor growth compared with sunitinib or c-Met inhibitor alone in resistant tumors. Histology and in vitro analyses suggested that combination treatment mainly targeted the vasculature in the resistant tumors. Conversely, systemic injection of HGF in the sensitive tumor models conferred resistance to sunitinib through maintenance of tumor angiogenesis. In conclusion, our study indicates a role for HGF/c-Met pathway in development of resistance to antiangiogenic therapy and suggests a potential strategy to circumvent resistance to vascular endothelial growth factor receptor tyrosine kinase inhibitor in the clinic.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 84%

HGF/c-Met Acts as an Alternative Angiogenic Pathway in Sunitinib-Resistant Tumors

et al. 2010

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“…Sorafenib, initially developed as a Raf kinase inhibitor, was later shown to inhibit several RTKs including VEGFRs and to show efficacy in renal cell cancer. SU11248 inhibits VEGFRs, PDGFR, c-kit, and Flt-3 and has efficacy in imatinib-resistant gastrointestinal stromal tumor (8) and renal cell carcinoma.…”

Section: Vascular Endothelial Growth Factor a Is A Key Regulator Of Pmentioning

confidence: 99%

Refractoriness to Antivascular Endothelial Growth Factor Treatment: Role of Myeloid Cells

Shojaei¹,

Ferrara²

2008

Cancer Research

153

129

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“…Many anticancer drugs cause direct damage to DNA, which triggers cellular checkpoints (4). In recent years, however, there has been a transition away from classic cytotoxic and hormonal agents toward targeted therapy (5). This involves the correction of precise molecular abnormalities that underlie the progression of the tumor.…”

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confidence: 99%

Drug resistance in cancer: Principles of emergence and prevention

Komarova

Wodarz²

2005

Proc. Natl. Acad. Sci. U.S.A.

391

349

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Although targeted therapy is yielding promising results in the treatment of specific cancers, drug resistance poses a problem. We develop a mathematical framework that can be used to study the principles underlying the emergence and prevention of resistance in cancers treated with targeted small-molecule drugs. We consider a stochastic dynamical system based on measurable parameters, such as the turnover rate of tumor cells and the rate at which resistant mutants are generated. We find that resistance arises mainly before the start of treatment and, for cancers with high turnover rates, combination therapy is less likely to yield an advantage over single-drug therapy. We apply the mathematical framework to chronic myeloid leukemia. Early-stage chronic myeloid leukemia was the first case to be treated successfully with a targeted drug, imatinib (Novartis, Basel). This drug specifically inhibits the BCR-ABL oncogene, which is required for progression. Although drug resistance prevents successful treatment at later stages of the disease, our calculations suggest that, within the model assumptions, a combination of three targeted drugs with different specificities might overcome the problem of resistance.multiple-drug therapy ͉ mutations ͉ stochastic models

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Emerging Roles of Targeted Small Molecule Protein-Tyrosine Kinase Inhibitors in Cancer Therapy

Cited by 87 publications

References 0 publications

HGF/c-Met Acts as an Alternative Angiogenic Pathway in Sunitinib-Resistant Tumors

HGF/c-Met Acts as an Alternative Angiogenic Pathway in Sunitinib-Resistant Tumors

Refractoriness to Antivascular Endothelial Growth Factor Treatment: Role of Myeloid Cells

Drug resistance in cancer: Principles of emergence and prevention

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