%0 Journal Article %A Rodrigo A. Toledo %A Elena Garralda %A Maria Mitsi %A Tirso Pons %A Jorge Monsech %A Estela Vega %A Álvaro Otero %A Maria I. Albarran %A Natalia Baños %A Yolanda Durán %A Victoria Bonilla %A Francesca Sarno %A Marta Camacho-Artacho %A Tania Sanchez-Perez %A Sofia Perea %A Rafael Álvarez %A Alba De Martino %A Daniel Lietha %A Carmen Blanco-Aparicio %A Antonio Cubillo %A Orlando Domínguez %A Jorge L. Martínez-Torrecuadrada %A Manuel Hidalgo %T Whole-exome sequencing of plasma cell-free DNA portrays the somatic mutation landscape of refractory metastatic colorectal cancer and enables the discovery of mutated KDR/VEGFR2 receptors as modulators of anti-angiogenic therapies %D 2017 %R 10.1101/177287 %J bioRxiv %P 177287 %X The non-invasive detection of cancer mutations is a breakthrough in oncology. Here, 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 VEGFR inhibitors, and identified the novel KDR/VEGFR2 L840F somatic mutation, which we showed was a clonal mutation event in this tumor. We found a 1-3% of recurrent KDR somatic mutations across large and non-overlapping cancer sequencing projects. Importantly, the majority of these mutations are located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK, suggesting a functional role. Comprehensive in vitro and in vivo functional assays confirmed that L840F causes strong resistance to anti-angiogenic drugs, whereas the KDR/VEGFR2 hot-spot mutant R1032Q confers sensitivity to cabozantinib. The current study implicates VEGFR2 cancer mutants as direct regulators of the efficacy of anti-angiogenic therapies. %U https://www.biorxiv.org/content/biorxiv/early/2017/08/17/177287.full.pdf