Integrins play a role in the resistance of advanced cancers to radiotherapy and chemotherapy. In this study, we show that high expression of the a5 integrin subunit compromises temozolomide-induced tumor suppressor p53 activity in human glioblastoma cells. We found that depletion of the a5 integrin subunit increased p53 activity and temozolomide sensitivity. However, when cells were treated with the p53 activator nutlin-3a, the protective effect of a5 integrin on p53 activation and cell survival was lost. In a functional p53 background, nutlin-3a downregulated the a5 integrin subunit, thereby increasing the cytotoxic effect of temozolomide. Clinically, a5b1 integrin expression was associated with a more aggressive phenotype in brain tumors, and high a5 integrin gene expression was associated with decreased survival of patients with high-grade glioma. Taken together, our findings indicate that negative cross-talk between a5b1 integrin and p53 supports glioma resistance to temozolomide, providing preclinical proof-of-concept that a5b1 integrin represents a therapeutic target for high-grade brain tumors. Direct activation of p53 may remain a therapeutic option in the subset of patients with high-grade gliomas that express both functional p53 and a high level of a5b1 integrin. Cancer Res; 72(14); 3463-70. Ó2012 AACR.

In EGFR-TKIs naive NSCLC patients, MET amplification is a frequent event, which could be associated with EGFR amplification, but not with K-Ras mutation. MET amplification may identify a subset of NSCLC for new targeted therapy. It will also be important to evaluate MET copy number to properly interpret future clinical trials.

The failure rate of randomized phase III oncology clinical trials is extremely high, even when preceded by encouraging preclinical studies and phase II trial results of the same therapy. Thus there is considerable effort being made to improve the predictive clinical potential of preclinical models, in addition to improving phase II trial design. With respect to the former, preclinical models have historically relied heavily on treatment of primary spontaneous or transplanted tumors rather than the more common and therapeutically challenging clinical trial circumstance of advanced metastatic disease. Here we show that the oral antiangiogenic tyrosine kinase inhibitor (TKI), sunitinib, which failed to meet primary or secondary survival endpoints in four separate phase III metastatic breast cancer (MBC) trials, either alone or with chemotherapy, similarly failed to show monotherapy or combination chemotherapy efficacy in a model of postsurgical advanced MBC, using a metastatic variant of the MDA-MB-231 triple negative human breast cancer. In contrast, the drug was effective when used to treat established orthotopic primary tumors. Similar results were obtained with pazopanib monotherapy, another antiangiogenic oral TKI. However, when an antibody targeting the VEGF pathway (DC101) was tested, it showed a trend in modestly improving the efficacy of paclitaxel therapy, thus resembling to a degree prior phase III clinical results of bevacizumab plus paclitaxel in MBC. Our results suggest the potential value of treating postsurgical advanced metastatic disease as a possible strategy to improve preclinical models for predicting outcomes in patients with metastatic disease.