Study Highlights Potential of Protein-Based Signaling Analysis in Cancer Treatment

Protein-based signaling analysis in metastatic breast cancer (MBC) patients may help predict treatment responses and guide therapeutic interventions, according to a study appearing this week in NPJ Precision Oncology. Endocrine therapy (ET) plus CDK4/6 inhibition is the typical first-line treatment for hormone-receptor positive, HER2 negative (HR+/HER2-) MBC, which represents the most common form of the disease. While this drug combination is effective in many patients, up to 40 percent of patient will progress quickly, creating an urgent need for new drug-response biomarkers. In the study, a team led by George Mason University researchers conducted a clinical trial to map the functional activation and signaling architecture of pretreatment tumor tissue biopsies collected from HR+/HER2- MBC patients receiving a CDK4/6 inhibitor plus ET. They found that phosphorylation levels of certain CDK4/6 downstream substrates were higher in patients with progressive disease versus those who responded to treatment. The investigators also uncovered genomic-independent activation of the AKT/mTOR pro-survival signaling pathway in tumor epithelia and stroma/immune cells of those with progressive disease. "As the number of FDA-approved therapies for MBC with HR+/HER2− disease expands from the ER and CDK4/6 directed landscape … a molecularly rationalized therapeutic selection process that captures activation levels of drug targets and substrates will become increasingly important given the disparate mechanisms of action of these therapies," the study's authors conclude.