Reference Detail

Ref Type Journal Article
PMID (29588308)
Authors Toledo RA, Garralda E, Mitsi M, Pons T, Monsech J, Vega E, Otero Á, Albarran MI, Baños N, Durán Y, Bonilla V, Sarno F, Camacho-Artacho M, Sanchez-Perez T, Perea S, Álvarez R, De Martino A, Lietha D, Blanco-Aparicio C, Cubillo A, Domínguez O, Martínez-Torrecuadrada JL, Hidalgo M
Title Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 24
Issue 15
Date 2018 Aug 01
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
D717V missense unknown KDR (VEGFR2) D717V lies within the Ig-like C2-type domain 7 of the Kdr (Vegfr2) protein (PMID: 19723655). The functional effect of D717V is conflicting, as D717V confers a gain of function to the Kdr (Vegfr2) protein, resulting in constitutive tyrosine autophosphorylation (PMID: 19723655), but does not induce tumor growth in cell line xenografted mice above wild-type (PMID: 29588308).
G800D missense gain of function - predicted KDR (VEGFR2) G800D lies within the cytoplasmic domain of the Kdr (Vegfr2) protein (UniProt.org). G800D has not been biochemically characterized, however, promotes tumor formation in xenograft models (PMID: 29588308), and therefore, is predicted to confer a gain of function to the Kdr (Vegfr2) protein.
G800R missense gain of function - predicted KDR (VEGFR2) G800R lies within the cytoplasmic domain of the Kdr (Vegfr2) protein (UniProt.org). G800R has not been biochemically characterized, however, promotes tumor formation in xenograft models (PMID: 29588308), and therefore, is predicted to confer a gain of function to the Kdr (Vegfr2) protein.
G843D missense gain of function - predicted KDR (VEGFR2) G843D lies within the protein kinase domain of the Kdr (Vegfr2) protein (UniProt.org). G843D has not been biochemically characterized, however, promotes tumor formation in xenograft models (PMID: 29588308), and therefore, is predicted to confer a gain of function to the Kdr (Vegfr2) protein.
L1049W missense unknown KDR (VEGFR2) L1049W lies within the protein kinase domain of the Kdr (Vegfr2) protein (UniProt.org). L1049W has been identified in the scientific literature (PMID: 29588308), but has not been biochemically characterized and therefore, its effect on Kdr (Vegfr2) protein function is unknown (PubMed, Jan 2019).
L840F missense unknown KDR (VEGFR2) L840F lies within the protein kinase domain of the Kdr (Vegfr2) protein (UniProt.org). The functional effect of L840F is conflicting, as it results in a loss of Kdr (Vegfr2) kinase activity in culture, but promotes tumor development in xenograft models, and is associated with resistance to Kdr (VEGFR2) inhibitors (PMID: 29588308). Y
R1022Q missense gain of function - predicted KDR (VEGFR2) R1022Q lies within the protein kinase domain of the Kdr (Vegfr2) protein (UniProt.org). R1022Q has not been biochemically characterized, however, promotes tumor formation in xenograft models (PMID: 29588308), and therefore, is predicted to confer a gain of function to the Kdr (Vegfr2) protein.
R1032Q missense unknown KDR (VEGFR2) R1032Q lies within the protein kinase domain of the Kdr (Vegfr2) protein (UniProt.org). The functional effect of R1032Q is conflicting, as R1032Q results in decreased ligand-induced phosphorylation of Kdr (Vegfr2) and Mapk in cell culture (PMID: 28743916), but induces tumor growth in cell line xenografted mice above wild-type (PMID: 29588308).
S1100F missense unknown KDR (VEGFR2) S1100F lies within the protein kinase domain of the Kdr (Vegfr2) protein (UniProt.org). The functional effect of S1100F is conflicting, as S1100F results in decreased ligand-induced phosphorylation of Krd (Vegfr2) and Mapk in cell culture (PMID: 28743916), but induces tumor growth in cell line xenografted mice above wild-type (PMID: 29588308).
S925F missense gain of function - predicted KDR (VEGFR2) S925F lies within the protein kinase domain of the Kdr (Vegfr2) protein (UniProt.org). S925F has not been biochemically characterized, however, promotes tumor formation in xenograft models (PMID: 29588308), and therefore, is predicted to confer a gain of function to the Kdr (Vegfr2) protein.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KDR L840F colorectal cancer resistant Sorafenib Preclinical - Pdx Actionable In a preclinical study, a metastatic colorectal cancer patient-derived xenograft (PDX) model harboring KDR (VEGFR2) L840F did not respond to treatment with Nexavar (sorafenib) (PMID: 29588308). 29588308
KDR R1032Q colorectal cancer sensitive Lenvatinib Preclinical - Cell culture Actionable In a preclinical study, expression of KDR (VEGFR2) R1032Q in a colorectal cancer cell line resulted in increased sensitivity to Lenvima (lenvatinib), leading to increased growth inhibition in culture (PMID: 29588308). 29588308
KDR L840F colorectal cancer resistant Regorafenib Preclinical - Pdx Actionable In a preclinical study, a metastatic colorectal cancer patient-derived xenograft (PDX) model harboring KDR (VEGFR2) L840F did not respond to treatment with Stivarga (regorafenib) (PMID: 29588308). 29588308
KDR R1032Q colorectal cancer sensitive Cabozantinib Preclinical - Cell culture Actionable In a preclinical study, Cometriq (Cabometyx, cabozantinib) inhibited reduced ERK phosphorylation and inhibited growth of a colorectal cancer cell line harboring KDR (VEGFR2) R1032Q in culture (PMID: 29588308). 29588308