YY1 downregulation underlies therapeutic response to molecular targeted agents

Abstract

During targeted treatment, oncogene-addicted tumor cells often evolve from initial drug-sensitive state through a drug-tolerant persister bottleneck towards the ultimate emergence of drug-resistant clones. The molecular basis underlying this therapy-induced evolutionary trajectory is not completely elucidated. Here, we employed a multifaceted approach and implicated a convergent role of transcription factor Yin Yang 1 (YY1) in the course of diverse targeted kinase inhibitors. Specifically, pharmacological perturbation of receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) pathway resulted in the downregulation of YY1 transcription, which subsequently resumed upon therapeutic escape. Failure to decrease YY1 subverted cytotoxic effects, whereas eliminating residual YY1 maximized anticancer efficacy and forestalled the emergence of drug resistance. Mechanistically, YY1 was uncovered to dictate cell cycle and autophagic programs. Immunohistochemical analysis on a wide spectrum of clinical specimens revealed that YY1 was ubiquitously expressed across lung adenocarcinomas and exhibited anticipated fluctuation in response to corresponding RTK/MAPK inhibition. These findings advance our understanding of targeted cancer management by highlighting YY1 as a determinant node in the context of genotype-directed agents.