Abstract
Colorectal cancer (CRC) is a common tumor type with a high mortality rate, in part due to intrinsic drug resistance. Although bevacizumab, a VEGF-directed neutralizing antibody, is particularly active in this pathology, some patients never respond for reasons not well understood. We here wish to clarify the role of autocrine VEGF signaling in the response of CRC cells to angiogenesis inhibition. Our results show that CRC cells with intrinsic bevacizumab-resistance displayed pronounced upregulation of autocrine HIF-VEGF-VEGFR signaling in response to prolonged bevacizumab exposure whereas the same signaling pathway was downregulated in bevacizumab-sensitive xenografts. Importantly, both bevacizumab-sensitive and -resistant CRC xenografts were sensitive to nintedanib, a small molecule angiokinase inhibitor, which was associated with inhibition of mTORC1. In vitro studies revealed that bevacizumab-resistant cells displayed intrinsically higher HIF-VEGF signaling intensity and hypoxia tolerance compared to their bevacizumab-sensitive counterparts. Interestingly, although nintedanib showed comparable activity toward bevacizumab-sensitive cells under normoxia and hypoxia, the drug was three-fold more toxic to the resistant cells under hypoxia, suggesting that nintedanib attenuated the survival signaling that usually protects these cells from hypoxia-mediated cell death. In conclusion, our findings support a role for autocrine VEGF signaling in the survival of CRC cells to hypoxia and thus to angiogenesis inhibition. We further show that nintedanib, a small molecule angiokinase inhibitor, is active toward CRC models with intrinsic bevacizumab resistance supporting clinical trials of nintedanib in patients that do not respond to bevacizumab, alone or in combination with bevacizumab to increase angiogenesis inhibition.
Highlights
Neovascularization is required for the growth of most solid tumors and facilitates the spread of tumor cells to secondary sites [1] providing a rational basis for the clinical use of angiogenesis inhibitors
These data suggest that the antitumor activity of at least some small molecule angiokinase inhibitors is not limited by the mechanisms underlying natural bevacizumab resistance and provide a rational for clinical trials of nintedanib in Colorectal cancer (CRC) patients that do not respond to bevacizumab, alone or in combination with bevacizumab to increase angiogenesis inhibition
Continued bevacizumab treatment of mice carrying human CRC xenografts revealed that HT-29 tumors are naturally bevacizumab-resistant with only 29% growth inhibition after 4 weeks drug exposure while the same scheduling resulted in 68% tumor growth inhibition for the bevacizumab-sensitive DLD-1 tumors (Figure 1A)
Summary
Neovascularization (sprouting angiogenesis) is required for the growth of most solid tumors and facilitates the spread of tumor cells to secondary sites [1] providing a rational basis for the clinical use of angiogenesis inhibitors. Vascular endothelial growth factor A (hereafter referred to as VEGF) is a key regulator of angiogenesis. Amplification of the VEGF locus is observed in a subset of patients with metastatic colorectal cancer (mCRC) and is associated with a remarkably aggressive disease characterized by a high incidence of vascular invasion www.impactjournals.com/oncotarget [2]. VEGF signaling is linked to invasiveness and aggressive disease in CRC and appears as an attractive therapeutic target. Several VEGF(R)-targeted agents are approved or are undergoing clinical trials for treatment of CRC. Bevacizumab (avastin), a VEGF-neutralizing monoclonal antibody [4], was the first angiogenesis inhibitor to be approved and represents the current benchmark. Nintedanib is currently in phase III clinical trials in ovarian and non-small cell lung cancer (NSCLC), where it has been successful in combination with taxotere [6]
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