Highlights of This Issue

Using a chemosensitivity RNA interference screen against 133 genes with known somatic mutations in breast cancer, Singel and colleagues identified the kinesin family member 14 (KIF14) and talin 1 as modulators of response to docetaxel in 4 triple-negative breast cancer cell lines but not in 3 hormonereceptor positive cell lines. Knockdown of these genes did not affect chemosensitivity to normal mammary epithelial cells. Their results show that high KIF14 expression is prognostic of poor relapse-free survival (946 patients) and poor overall survival (652 patients). Therefore, decreasing expression of these genes is an attractive target to sensitize triple negative human breast cancer cells to taxane treatment.

Induction of the viral lytic cycle is a promising strategy for treatment of Epstein–Barr virus (EBV)–driven malignancies because viral lytic replication is associated with death of EBV-carrying tumor cells. Giunco and colleagues show that inhibition of human telomerase reverse transcriptase (hTERT), the catalytic component of telomerase, promotes induction of the viral lytic cycle and triggers apoptosis of EBV-immortalized and fully transformed B cells. These results provide the rationale to activate clinical studies based on the combination of antiviral drugs with inhibitors of hTERT expression/activity for the treatment of EBV-driven malignancies.

The multikinase inhibitor sorafenib successfully displayed antitumor activity in preclinical models of metastatic osteosarcoma. Unfortunately, in the clinical setting tumor shrinkage and disease stabilization with sorafenib were short-lived, owing to drug resistance. Pignochino and colleagues showed mTOR complex 2 (mTORC2) upregulation in sorafenib-treated osteosarcoma models, thereby suggesting a potential escape mechanism. The combination of sorafenib with the mTOR inhibitor everolimus achieved total blockage of both mTORC1 and mTORC2 through an increase of reactive oxygen species and the activation of AMP-dependent kinase. This complete inhibition eventually enhances the antitumor, antimetastatic, and antiangiogenic effects in osteosarcoma xenograft models.

In a phase II clinical study in metastatic colorectal cancer, Amatu and colleagues show for the first time that dacarbazine activity is confined to patients with tumors defective in O⁶-methylguanine-DNA-methyltransferase function due to promoter CpG hypermethylation. In the context of cancer science, these data therefore highlight a previously unidentified subgroup of patients with colorectal cancer who benefit from treatment with methylating agents based on a specific epigenetic alteration in individual tumors. This is a step in the direction of personalized cancer medicine.