CYP3A4-mediated metabolic variability drives resistance and systemic toxicities under targeted therapies for non–small cell lung cancer

Further, although targeted therapies are typically well tolerated, a subset of patients displays dose-limiting adverse effects. Therapy resistance is generally considered to be a tumor-intrinsic phenomenon, mediated by cell-intrinsic or microenvironmental mechanisms.

We found that hyperactivation of CYP3A4, a P450 family enzyme, can lead to tumor-extrinsic resistance by altering pharmacokinetics and reducing systemic and tumor drug exposure, whereas reduced CYP3A4 activity is expected to increase systemic toxicities. Retrospective analysis of clinical cohorts suggests that variability in CYP3A4 activity might be a major contributor to variability in clinical outcomes. To understand the consequences of altered drug metabolism, we developed a mathematical model linking variability in CYP3A4 activity with temporal variability in systemic drug concentrations.