TP53 Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics
Open Access
- 1 October 2016
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 15 (10), 2475-2485
- https://doi.org/10.1158/1535-7163.mct-16-0196
Abstract
TP53 tumor-suppressor gene mutations are among the most frequent abnormalities in cancer, affecting approximately 40% of patients. Yet, there is no accepted way to target these alterations in the clinic. At the same time, antagonists of VEGFR or its ligand are best-selling oncology drugs, with multiple, expensive compounds approved. Although only a subset of patients benefit from these antiangiogenesis agents, no relevant biomarker has been identified. Interestingly, TP53 mutations upregulate VEGF-A and VEGFR2. We prospectively enrolled 500 patients, to be interrogated by comprehensive genomic profiling (CGP) (next-generation sequencing, 236 genes), and to be matched, whenever possible, with targeted agents. Herein, we analyze outcomes based on VEGF/VEGFR inhibitor treatment and presence of TP53 mutations. Of the 500 patients, 188 (37.6%; with ≥1 alteration) were treated; 106 (56% of 188) had tumors that harbored TP53 mutations. VEGF/VEGFR inhibitor therapy was independently associated with improvement in all outcome parameters [rate of stable disease (SD) ≥6 months/partial and complete remission (PR/CR); (31% versus 7%; TP53-mutant patients (who received no other molecular-matched agents) treated with versus without VEGF/VEGFR inhibitors), time-to-treatment failure, and overall survival (multivariate analysis: all P ≤ 0.01)] for the patients harboring TP53-mutant cancers, but improvement was not seen in any of these parameters for patients with TP53 wild-type neoplasms. We conclude that TP53 mutations predict sensitivity to VEGF/VEGFR inhibitors in the clinic. TP53 alterations may therefore be a ready biomarker for treatment with antiangiogenesis agents, a finding of seminal importance across the cancer field. Mol Cancer Ther; 15(10); 2475–85. ©2016 AACR.Keywords
Other Versions
This publication has 45 references indexed in Scilit:
- The p53 family and VEGF regulation: “It’s complicated”Cell Cycle, 2013
- Mutant p53 protein, master regulator of human malignancies: a report on the fifth Mutant p53 WorkshopCell Death & Differentiation, 2011
- Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients With Medullary Thyroid CancerJournal of Clinical Oncology, 2011
- Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of TumorigenesisGenes & Cancer, 2011
- Mutant p53 Gain-of-Function in CancerCold Spring Harbor Perspectives in Biology, 2009
- Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction to Reactivate p53 Function: A Novel Approach for Cancer TherapyAnnual Review of Pharmacology and Toxicology, 2009
- Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGFProceedings of the National Academy of Sciences of the United States of America, 2006
- Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancerNature Reviews Drug Discovery, 2004
- Nonparametric Estimation from Incomplete ObservationsJournal of the American Statistical Association, 1958
- Nonparametric Estimation from Incomplete ObservationsJournal of the American Statistical Association, 1958