Deciphering the anticancer mechanisms of sunitinib

Abstract

Commentary to:

SU11248, A selective tyrosine kinases inhibitor suppresses breast tumor angiogenesis and growth via targeting both tumor vasculature and breast cancer cells

Emily Young, Lucio Miele, Kevan B Tucker, Min Huang, Jeremy Wells and Jian-Wei Gu

The utility of targeted agents in breast cancer has been recognized for decades. In 1952, Huggins reported modulation of endocrine axes via adrenalectomy as a means of inducing tumor regression.1 Since then, selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) have dramatically improved clinical outcome in patients with hormone-receptor positive disease.2 Similarly, identification of the HER2/neu proto-oncogene in approximately 25% of patients with breast cancer ushered in agents, such as trastuzumab and lapatinib, directed at this moiety.3 Within the past several years, vascular endothelial growth factor (VEGF) targeted therapies have also been incorporated into the treatment paradigm of advanced breast cancer. Several phase III trials combining the VEGF-directed antibody bevacizumab with cytotoxic chemotherapy have demonstrated significant clinical benefit.4,5 In contrast to bevacizumab, the clinical utility of VEGF receptor tyrosine kinase inhibitors (VEGFR-TKIs) is less understood in the setting of breast cancer. A key to optimizing the potential use of these agents is to better understand their mechanism of action—already, multiple alternate mechanisms to direct VEGFR antagonism have been proposed (Fig. 1). In this issue, Young et al. provide preclinical evidence suggesting the role of the VEGFR-TKI, sunitinib, in mediating both autocrine and paracrine effects in a heterogeneous array of breast cancer cell lines.6

Young et al. first demonstrate the antitumor efficacy of sunitinib in murine xenograft models.6 Female immunocompetent mice were injected with mouse breast adenocarcinoma (E0771) cells, and one of two cohorts received sunitinib via oral gavage. Tumor cross-sectional area was reduced by 48% in the sunitinib-treated group as compared to the control group. Morphometric analyses further suggest a decrease in microvessel density with sunitinib therapy. Illustrating a distinct antitumor mechanism of sunitinib, migration assays performed on the E0771 breast cancer cell line demonstrated impaired tumor motility with sunitinib therapy. Does the antitumor effect of sunitinib extend beyond the estrogen receptor (ER)-positive E0771 cell line? To this end, Young et al. further assessed ER-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cell lines. In comparing the two, MDA-MB-231 cells had higher VEGF and VEGFR-1 expression. While higher doses of sunitinib (10 µmol/L) led to similar growth inhibition in both MCF-7 and MDA-MB-231 cells, treatment with lower doses of sunitinib (5 µmol/L) had a more substantial effect on MCF-7 cells. These results suggest a differential antitumor effect of sunitinib based on ER status; certainly, further validation is necessary to confirm this finding.

In line with the report by Young et al. a substantial literature has amassed suggesting that a direct antitumor effect of sunitinib complements an effect on the microenvironment—a unifying hypothesis may be inhibition of signal transducer and activator of transcription 3 (Stat3). Xin et al. have demonstrated a correlation between sunitinib-induced Stat3 inhibition and tumor apoptosis in the Renca human renal cell carcinoma (RCC) cell line.7 Furthermore, sunitinib appears to inhibit Stat3 in Renca tumor-associated myeloid-derived suppressor cells (MDSCs). Perhaps as a consequence, accumulation of MDSCs (along with regulatory T cells and other immune cells) is blunted at the site of tumor. Clinical support of these observations is derived from a report by Finke et al. examining metastatic RCC patients treated with sunitinib.8 Peripheral blood collected on days 1 and 28 of therapy show a diminution in regulatory T-cell percentage with a concomitant increase in the type-1 T-cell cytokine response. Several reports utilizing non-RCC models suggest a similar effect of sunitinib on inhibitory immune cells, thereby possibly potentiating an anti-tumor immune response.

While Young et al. specifically describe antagonism of VEGFR by sunitinib, targeting of other receptors may contribute to the activity of the agent. Outside of VEGFR-1 and -2, preclinical studies across multiple cell lines have demonstrated IC₅₀ values in the nanomolar range for c-kit, flt3 and RET.9 Targeting of these distinct receptors may portend increased activity in certain diseases. As an example, the response to sunitinib in imatinib-resistant gastrointestinal stromal tumor (GIST) is enhanced amongst patients who bear specific mutations in the exons coding for KIT.10,11 Thus, VEGFR antagonism alone may not fully explain the antitumor effect of sunitinib.12

A more comprehensive understanding of sunitinib's mechanism of action lends itself to identifying patients that are more prone to benefit from therapy. This may be particularly important in the setting of breast cancer, where the efficacy of the single agent appears to be modest. In a phase II trial of sunitinib therapy in pre-treated patients with advanced breast cancer, an overall response rate of 11% was observed.13 A subsequently reported trial comparing sunitinib therapy to single agent capecitabine in the setting of HER2-negative metastatic disease was terminated due to futility in reaching the primary endpoint (progression-free survival).14 Furthermore, efforts to combine sunitinib with other clinically relevant targeted agents have been challenging—for example, the phase II SABRE-B trial comparing paclitaxel and bevacizumab with or without sunitinib was closed prematurely due to concerns related to toxicity.15 With the fate of sunitinib in breast cancer still hanging in the balance, a mechanistic understanding may ultimately lead to biomarkers that allow the clinician to select patients best suited for therapy with this agent.

Figures and Tables

Figure 1 Suggested mechanisms of the VEGFR-TKI sunitinib.

Acknowledgements

S.K.P. efforts are supported by the NIH Loan Repayment Plan (LRP), the CBCRP 15IB-0140 (California Breast Cancer Research Program Junior IDEA Award) and NIH K12 2K12CA001727-16A1.

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