Clinical Response to Pazopanib in a Patient With <i>KDR</i>-Mutated Metastatic Basal Cell Carcinoma

Knepper, Todd C.; Freeman, Morganna; Gibney, Geoffrey T.; McLeod, Howard L.; Russell, J S

doi:10.1001/jamadermatol.2017.0187

Cited by 11 publications

(11 citation statements)

References 6 publications

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“…In agreement with our preclinical experimental findings, Knepper and colleagues very recently reported a prolonged complete response to pazopanib in a metastatic basal cellular carcinoma patient carrying the KDR/VEGFR2 R1032Q somatic mutation (16). Interestingly, a second mCRC patient case with the KDR/VEGFR2 R961W somatic mutation was also recently reported.…”

Section: Discussionsupporting

confidence: 91%

Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Toledo

Garralda

Mitsi

et al. 2018

Clinical Cancer Research

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Despite the wide use of antiangiogenic drugs in the clinical setting, predictive biomarkers of response to these drugs are still unknown. We applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a 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. WES-cfDNA yielded a 77% concordance rate with tumor exome sequencing and enabled the identification of the /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 somatic mutations located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK. Our and functional assays confirmed that L840F causes strong resistance to antiangiogenic drugs, whereas the 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. 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. .

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Section: Discussionsupporting

confidence: 91%

Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Toledo

Garralda

Mitsi

et al. 2018

Clinical Cancer Research

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“…A case report showed a CR to pazopanib (a potent VEGFR inhibitor) in a patient with metastatic BCC who was treated after NGS demonstrated the tumor harbored a KDR gene mutation, a gene which encodes VEGFR-2 [65].…”

Section: Other Targetsmentioning

confidence: 99%

Advanced basal cell cancer: concise review of molecular characteristics and novel targeted and immune therapeutics

et al. 2018

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Metastatic basal cell carcinoma is an ultra-rare manifestation of a common disease, appearing in 0.0028% to 0.5% of basal cell carcinomas. Initial therapeutic efforts focused on cytotoxic chemotherapy administration. However, it is now known that the Hedgehog signaling pathway is crucial for basal cell proliferation and Hedgehog pathway mutations may lead to tumorigenesis; thus, small molecule inhibitors of alterations in the components of this pathway, including smoothened (SMO) and GLI, have been the focus of recent therapeutic developments. Indeed, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have approved the SMO inhibitors, vismodegib and sonidegib, with additional GLI inhibitors currently in clinical trials. Molecular profiling of these tumors has revealed other potential targets for therapy, including high tumor mutational burden and PD-L1 amplification, which predict response to immune checkpoint blockade (PD-1 and PD-L1 inhibitors). An illustrative patient with a giant, advanced, unresectable basal cell carcinoma who obtained an ongoing complete remission after treatment with a combination of an immune checkpoint inhibitor (due to the tumor's high mutational burden) and the Hedgehog inhibitor vismodegib is described. A fuller understanding of the genomic portfolio of these patients can assist in developing novel, rational therapeutic approaches that should continue to improve responses and outcomes.

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“…This approach has allowed the detection and characterization of previously unknown oncogenic and/or actionable cancer variants of tyrosine kinase receptors (RTKs), including TGFBR, HER2 and VEGFR2 [7,8], a protein family commonly dysregulated in tumors and an important target for cancer therapy [9,10]. Remarkably, case reports and NGS analyses have previously described various mutations of VEGFR2, including L840F, R961W, R1032Q and S1100F, some of which correlate with tumor growth and altered response to tyrosine kinase inhibitors (TKi) [7,11,12].…”

Section: Introductionmentioning

confidence: 99%

A novel variant of VEGFR2 identified by a pan-cancer screening of recurrent somatic mutations in the catalytic domain of tyrosine kinase receptors enhances tumor growth and metastasis

et al. 2021

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Clinical Response to Pazopanib in a Patient With KDR-Mutated Metastatic Basal Cell Carcinoma

Cited by 11 publications

References 6 publications

Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Advanced basal cell cancer: concise review of molecular characteristics and novel targeted and immune therapeutics

A novel variant of VEGFR2 identified by a pan-cancer screening of recurrent somatic mutations in the catalytic domain of tyrosine kinase receptors enhances tumor growth and metastasis

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