In Cancer Discovery this week, researchers at Genentech and the BC Cancer Agency report that the p27 phosphatase PPM1H is implicated in trastuzumab resistance in some breast cancer patients. Through RNA interference screening, the team found that knocking down PPM1H conferred trastuzumab resistance by reducing protein levels of the tumor suppressor p27. In addition, the authors write, they determined that patients whose tumors express low levels of PPM1H trend toward worse clinical outcomes when treated with trastuzumab. "Low PPM1H expression may identify a subset of HER2-positive tumors that are harder to treat," the researchers add.
Also in Cancer Discovery this week, researchers from the US and Europe say ER-alpha-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Most ER-positive breast cancers initially respond to anti-estrogens, but can become estrogen independent and recur. In this study, the researchers identified an estrogen-independent role for ER and the CDK4/Rb/E2F transcriptional axis in the hormone-independent growth of breast cancer cells. "Gene expression profiling revealed an estrogen-independent, ER/E2F-directed transcriptional program. An E2F activation gene signature correlated with a lesser response to aromatase inhibitors in patients' tumors," the authors write. "siRNA screening showed that CDK4, an activator of E2F, is required for estrogen-independent cell growth." This data supports the development of ER down-regulators and CDK4 inhibitors for the treatment of anti-estrogen-resistant breast cancer, the team adds.
Finally in Cancer Discovery this week, researchers in the US and Peru find that BIM expression in treatment-naïve cancers can predict responsiveness to kinase inhibitors. The team measure apoptotic rates among cell lines sharing the same driver oncogene, following treatment with a corresponding kinase inhibitor. The researchers found that there was a wide range of kinase inhibitor-induced apoptosis. "Surprisingly, pretreatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR-mutant, HER2-amplified, and PIK3CA-mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies," the authors write. "Furthermore, BIM RNA levels in EGFR-mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors.