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Molecular basis for sunitinib efficacy and future clinical development

Key Points

  • Vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs) and stem-cell growth factor receptor (KIT) are tyrosine kinases that have a major role in tumour cell proliferation and angiogenesis.

  • Sunitinib (Sutent; Pfizer), a novel oral multitargeted tyrosine kinase receptor inhibitor blocks the activation of VEGFRs 1–3, PDGFRα, PDGFRβ, KIT, fms-related tyrosine kinase 3 (FLT3), RET and colony-stimulating factor receptor 1 (CSF1R), resulting in anti-angiogenic and antitumor activity against a broad range of malignancies.

  • Sunitinib has been registered as a first-line therapy in patients with advanced renal cell carcinoma, as well as in imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumours (GISTs).

  • Sunitinib may be used at the dose of 50 mg per day on an intermittent 4-week on/2-week off schedule, or continuously at the dose of 37.5 mg per day with a safe toxicity profile.

  • In addition to tumour shrinkage that can be easily evaluated according to RECIST criteria, changes in tumour density may reflect sunitinib antitumor activity, requiring additional imaging criteria.

  • Promising results have been reported in other tumour types including hepatocellular carcinoma and neuroendocrine tumours.

  • Resistance to sunitinib may require mutations of tyrosine kinase as demonstrated for KIT in GIST, as well as evasion of VEGF/VEGFR-dependent signalling pathways in tumour or endothelial cells.

  • Combinations with other targeted therapy and/or chemotherapy may broaden the spectrum of activity and/or circumvent resistance to sunitinib.

Abstract

Sunitinib malate (SU11248/Sutent; Pfizer) is a multitargeted tyrosine kinase inhibitor that has potent anti-angiogenic and antitumour activities. Definitive efficacy has been demonstrated in advanced renal cell carcinoma and in gastrointestinal stromal tumours that are refractory or intolerant to imatinib (Gleevec; Novartis), which has provided the basis for the recent regulatory approvals for these indications. This article summarizes the discovery and development of sunitinib, and discusses key issues for the multitargeted approach in cancer treatment, such as markers of response and development of resistance, and their significance for the future development of sunitinib and other multikinase inhibitors.

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Figure 1: Tyrosine kinase receptors involved in angiogenesis and lymphangiogenesis targeted by sunitinib.
Figure 2: Properties of sunitinib malate.
Figure 3: Effects of sunitinib on angiogenesis-associated cells and cancer cells.
Figure 4: Proposed mechanism of sunitinib-induced tumour necrosis.
Figure 5: Resistance to sunitinib.

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Acknowledgements

The authors would like to thank E. Eaton for medical writing assistance in the preparation of this manuscript.

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Correspondence to Eric Raymond.

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Competing interests

S.F., G.M. and E.R. are all consultants for Pfizer. W.S. was a former employee of Pfizer.

Supplementary information

Supplementary information S1 (table)

Summary of adverse events in the Phase III placebo-controlled GIST study (4/2 schedule of treatment administration). (PDF 168 kb)

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DATABASES

OMIM

acute myeloid leukaemia

breast cancer

chronic myeloid leukaemia

gastrointestinal stromal tumours

non-small-cell lung cancer

renal cell carcinoma

FURTHER INFORMATION

Sunitinib official web site

Glossary

Angiogenesis

The formation of new blood vessels from pre-existing ones. Also termed neovascularization.

Receptor tyrosine kinases

A family of transmembrane receptors that are physiologically activated by the extracellular binding of growth factor(s), and which initiate intracellular signalling.

Imatinib

(Gleevec; Novartis). An inhibitor of BCR–ABL, stem-cell factor receptor (KIT) and platelet-derived growth factor receptor (PDGFR). Approved for Philadelphia-chromosome-positive chronic myeloid leukaemia and KIT-positive unresectable/metastatic gastrointestinal stromal tumour (GIST).

Erlotinib

(Tarceva; Genentech/OSI Pharmaceuticals). An inhibitor of epidermal growth factor receptor (EGFR). Approved for second-line treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC).

Gefitinib

(Iressa; AstraZeneca). An inhibitor of EGFR. Approved as monotherapy for continued treatment of locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies.

Sorafenib

(Nexavar; Bayer/Onyx). An inhibitor of vascular endothelial growth factor receptor (VEGFR2 and VEGFR3), PDGFRβ, KIT, fms-like tyrosine kinase 3 (FLT3), RAF1 and BRAF kinases. Approved for advanced renal cell carcinoma (RCC).

Sunitinib

(Sutent; Pfizer). An inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRα, PDGFRβ, KIT, FLT3, RET and colony-stimulating factor receptor 1 (CSF1R). Approved for advanced RCC and imatinib-refractory GIST.

Pericytes

Cells related to vascular smooth muscle that are adjacent to and surround the endothelium, share a common basement membrane with the endothelium and have gap-junction connections with the endothelial cells.

Tumour-associated macrophages

Monocytes are continually recruited into tumours and differentiate into tumour-associated macrophages. These accumulate in hypoxic areas and can upregulate transcription factors, which in turn activate various mitogenic, pro-invasive, pro-angiogenic and pro-metastatic genes.

Oncogene

A mutated and/or overexpressed version of a normal gene that in a dominant manner can release the cell from the normal restraints of growth and thus, alone or together with other changes, convert a cell into a tumour cell.

Hypoxia-inducible transcription factor 1

(HIF1). A heterodimeric transcription factor that has a key role in the response to hypoxic stress. It is composed of HIFα and HIFβ subunits (HIFα has at least three isoforms: HIFα, HIFα and HIFα).

von Hippel–Lindau

(VHL). A tumour suppressor gene that is an important regulator of HIF. In renal cell carcinoma, defective function of VHL ablates proteolytic regulation of HIFα and HIFα, leading to constitutive activation of hypoxia pathways.

Endothelial progenitor cells

Undifferentiated cells in the adult bone marrow that can travel through the blood to sites of ongoing angiogenesis, and differentiate into mature endothelial cells.

Vasculogenesis

The formation of new blood vessels within previously avascular tissue.

Cytogenetic abnormalities

Abnormalities in chromosomal DNA (karyotype).

Lymphangiogenesis

Lymphatic vascular structures organized to collect extravased fluids, macromolecules and leukocytes at regional lymph nodes.

Hypoxia-induced necrosis

The accidental death of cells and living tissue due to oxygen depletion.

4/2 schedule

A four weeks on treatment, two weeks off treatment cycle.

Objective response rate

(ORR). The proportion of patients with complete or partial responses. Clinical response (complete response, partial response, stable disease and progressive disease) was assessed according to response evaluation criteria in solid tumours (RECIST).

Hand–foot syndrome

Characterized by tingling and/or numbness, swelling and redness of the palms and soles. In severe cases, the skin may peel, develop ulcerations or blisters and cause severe pain. Also known as palmar–plantar erythrodysesthesia.

Grade

The severity of adverse events is categorized according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 2.0 and Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (grade 1 is the least severe and 4 is the most severe).

RECIST criteria

Response evaluation criteria in solid tumours (RECIST) are used to evaluate the antitumour activity of novel anticancer agents in clinical trials. Evaluation of the tumour is made according to the longer diameters of target lesions.

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Faivre, S., Demetri, G., Sargent, W. et al. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 6, 734–745 (2007). https://doi.org/10.1038/nrd2380

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