VEGF-A Expression Correlates with TP53 Mutations in Non–Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy

Abstract

Bevacizumab is one of the most widely used antiangiogenic drugs in oncology, but the overall beneficial effects of this VEGF-A targeting agent are relatively modest, in part due to the lack of a biomarker to select patients most likely to respond favorably. Several molecular aberrations in cancer influence angiogenesis, including mutations in the tumor suppressor gene TP53, which occur frequently in many human malignancies. In this study, we present a multiple regression analysis of transcriptomic data in 123 patients with non-small cell lung cancer (NSCLC) showing that TP53 mutations are associated with higher VEGF-A expression (P ¼ 0.006). This association was interesting given a recent retrospective study showing longer progression-free survival in patients with diverse tumors who receive bevacizumab, if tumors harbor mutant TP53 instead of wild-type TP53. Thus, our current findings linking TP53 mutation with VEGF-A upregulation offered a mechanistic explanation for why patients exhibit improved outcomes after bevacizumab treatment when their tumors harbor mutant TP53 versus wild-type TP53. Overall, this work warrants further evaluation of TP53 as a ready biomarker to predict bevacizumab response in NSCLC and possibly other tumor types. Cancer Res; 75(7);

TP53Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics

“…Relatedly, mutant p53 cooperates with the SWI/SNF complex, which is essential for remodeling the VEGFR2 promoter. Given that wild-type TP53 is a canonical repressor of the VEGF pathway through multiple mechanisms, including transcriptional repression of VEGF-A (7,19,31,32), loss of wild-type p53 function/presence of mutant p53 has several mechanisms by which to turn on the angiogenic "switch." These mechanisms are compatible with increased susceptibility of TP53-mutant tumors to the effects of VEGF or VEGFR antagonists (5,33) as confirmed in the current investigation.…”

“…Recently, TP53 mutational status was also shown to be predictive of response to the VEGFR inhibitor pazopanib in advanced sarcomas (45). The underlying mechanism of response may relate to TP53 mutations being associated with upregulation of VEGF-A and VEGFR2 expression (7,(30)(31)(32). Of interest in this regard, other tumor suppressors that are not directly druggable may also be actionable based on the upregulation of affected pathways when the suppressor gene is mutated (46).…”

“…The mechanism by which this correlation might occur remains uncertain; however, there is evidence to suggest that TP53 is implicated in angiogenesis. For instance, a multiple regression analysis of the transcriptome in non-small cell lung cancer (NSCLC) revealed that high VEGF-A expression correlated independently with TP53 mutational status (7). Though early data failed to find a clear association between VEGF expression and outcome after bevacizumab administration, recent observations using improved technology indicate that circulating levels of the short isoform of VEGF-A is a strong biomarker candidate for predicting benefits (3).…”

Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing

“…TP53 alterations have been identified as early events in the carcinogenesis of ESCC and have been associated with disease progression and a poor outcome [42][43][44] . Therapies targeting TP53 loss of function are currently being examined in clinical trials, and several studies suggest that patients harboring TP53 alterations will respond better to angiogenesis inhibitors [45] . The efficacy of intra-tumor injection of p53 adenovirus (Advexin, Introgen Therapeutics Inc., Austin, TX, United States) has been confirmed in Japanese ESCC patients [46] .…”

Squamousness: Next-generation sequencing reveals shared molecular features across squamous tumor types

“…11 Therapies targeting TP53 loss of function are currently being explored in clinical trials, and several studies suggest that patients harboring TP53 alterations might respond better to angiogenesis inhibitors. 14,15 Of note, a TP53 adenoviral-based treatment (rAd-p53; Gendicine) for patients with HNSCC has recently been approved for use in China. 16 Cyclin-dependent kinase inhibitor 2A (CDKN2A), located at chromosome 9p21, is another well-known tumor suppressor gene involved in the regulation of cell cycle progression and was altered in 24.5% of our SCC cases.…”