Abstract

Purpose: Despite the wide use of antiangiogenic drugs in the clinical setting, predictive biomarkers of response to these drugs are still unknown.Experimental Design: We applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens, including inhibitors to the VEGF:VEGFR2 pathway. We performed extensive functional experiments, including ectopic expression of VEGFR2 mutants in different cell lines, kinase and drug sensitivity assays, and cell- and patient-derived xenografts.Results: WES-cfDNA yielded a 77% concordance rate with tumor exome sequencing and enabled the identification of the KDR/VEGFR2 L840F clonal, somatic mutation as the cause of therapy refractoriness in our patient. In addition, we found that 1% to 3% of samples from cancer sequencing projects harbor KDR somatic mutations located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK. Our in vitro and in vivo functional assays confirmed that L840F causes strong resistance to antiangiogenic drugs, whereas the KDR hot-spot mutant R1032Q confers sensitivity to strong VEGFR2 inhibitors. Moreover, we showed that the D717V, G800D, G800R, L840F, G843D, S925F, R1022Q, R1032Q, and S1100F VEGFR2 mutants promote tumor growth in mice.Conclusions: Our study supports WES-cfDNA as a powerful platform for portraying the somatic mutation landscape of cancer and discovery of new resistance mechanisms to cancer therapies. Importantly, we discovered that VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs. Clin Cancer Res; 24(15); 3550-9. ©2018 AACR.

Highlights

  • Colorectal cancer is currently the third most frequent cancer diagnosed worldwide and is predicted to reach 2.2 million new cases per year by 2030 [1]

  • Some studies have suggested the potential association of tumor response with VEGF/VEGFR germline polymorphisms [5], these results could not be confirmed in subsequent assessments [6]

  • As R1032Q affects the universal kinase catalytic motif DxxxxN, and not the ATP-binding site as the L840F, we investigated whether R1032Q VEGFR2 would be inhibited by TKIs

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Summary

Introduction

Colorectal cancer is currently the third most frequent cancer diagnosed worldwide and is predicted to reach 2.2 million new cases per year by 2030 [1]. The identification of predictive biomarkers of the response to bevacizumab, as well as to new agents targeting VEGFR2, such as regorafenib, is still a fundamental unmet medical necessity [4]. Some studies have suggested the potential association of tumor response with VEGF/VEGFR germline polymorphisms [5], these results could not be confirmed in subsequent assessments [6]. Recent in vitro studies demonstrated that VEGFR2 plays a prominent role in endothelial cells, as is usually assumed, and in cancer cells [7].

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