A mechanism for adaptive genome regulation in cancer.

Abstract

The ability of cancer cells to consistently escape therapy highlights their remarkable adaptive potential. A longstanding debate in cancer research concerns whether drug resistance originates primarily from mutational processes or through cellular plasticity. Emerging evidence has suggested that adaptive cellular states arise through phenotypic plasticity triggered by intracellular stress signals. Here we propose a theoretical framework for how such cellular adaptation in cancer drug resistance could be 'learned' by the AP-1 family of transcription factors. We highlight key AP-1 properties, including regulatory combinatorics, stress-induced feedback and cellular memory, and argue that this system constitutes a molecular framework for establishing drug-resistant cellular states. Finally, we discuss the potentially broad relevance of this adaptation mechanism beyond cancer.