Highlights of This Issue

DOI: Published February 2010

Cancer Cell Line Evolution

Zhang et al., Page 336

Tumorigenesis is influenced by natural selection processes, thus molecular evolutionary methodologies could be useful for understanding cancer biology. Zhang and colleagues describe a phylogenetic analysis of 353 cancer cell lines based on the alignment of 3252 variant nucleotides from 494 genes from 353 cancer cell lines. Reconstructed phylogenetic trees clustered cell lines by shared DNA variant patterns rather than tissue, suggesting that certain diverse cancer types have similar oncogenic pathways. Positive selection analysis revealed specific DNA variants that might be potential driver mutations. Their study supports the broader application of evolutionary approaches in the analyses of the cancer genome.

RelA-Mediated Acquired Resistance to Lapatinib

Xia et al., Page 292

The clinical efficacy of lapatinib, a small molecule inhibitor of ErbB2 and EGFR tyrosine kinases, is limited by the development of therapeutic resistance. Xia and colleagues show that lapatinib unexpectedly activated RelA/NF-κB in ErbB2⁺ breast cancer cell lines and in ErbB2⁺ breast cancer patients. Inhibition of RelA phosphorylation led to increased apoptosis in lapatinib-treated ErbB2⁺ breast cancer cells. Furthermore, increased phospho-RelA expression in tumors treated with lapatinib monotherapy correlated with a poorer clinical outcome in ErbB2⁺ breast cancer patients. These findings identify RelA as a promising therapeutic target to enhance the clinical efficacy of lapatinib in ErbB2⁺ breast cancers.

Plk1 for Gemcitabine Resistance in Pancreatic Cancer

Jimeno et al., Page 311

Approaches to improve standard chemotherapeutic regimens by defining combinations are still empiric. Jimeno and colleagues evaluated a rational way of identifying relevant targets involved in the vulnerability of pancreatic cancer to gemcitabine. Pancreatic xenograft samples with known gemcitabine sensitivity were dynamically interrogated by exposure to gemcitabine and analysis of a preselected set of druggable genes. This identified Plk1 as a target dictating the susceptibility of pancreatic cancer to gemcitabine. Mechanistic studies aimed at testing this hypothesis were conducted utilizing gene interference and pharmacologic Plk1 inhibition, followed by in vivo testing in a direct xenograft model of pancreatic cancer.

Brivanib Antiangiogenesis Activity in Human Xenografts

Bhide et al., Page 369

Brivanib is an oral, dual selective inhibitor of VEGF and FGF signaling under clinical investigation. Bhide and colleagues evaluated the antitumor activity and antiangiogenic activities of brivanib and its prodrug brivanib alaninate in xenograft models and Matrigel plug assays in athymic mice. Brivanib and brivanib alaninate demonstrated potent antitumor and antiangiogenic activity over multiple dose levels in a broad range of tumor types. Further, brivanib alaninate inhibited angiogenesis driven by VEGF or bFGF alone, or when both growth factors were combined. This data supports the utility of targeting both VEGF- and FGF-induced angiogenesis in solid tumors.