Adaptive responses to <i>mTOR</i> gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition
Cuiqing Fan, Chuntao Zhao, Feng Zhang, Meenu Kesarwani, Zhaowei Tu, Xiongwei Cai, Ashley Kuenzi Davis, Lingli Xu, Cindy L. Hochstetler, Xiaoyi Chen, Fukun Guo, Gang Huang, Mohammad Azam, Weidong Tian, Q. Richard Lu, Yi Zheng
Abstract
Significance mTOR plays a critical role in regulating cell growth and is an important anticancer target. Numerous studies using mTOR inhibitors have shown that mTOR targeting suppresses gene expression and cell proliferation. However, mTOR-targeted cancer therapies have seen very limited success, and evasive resistance to mTOR-targeted drugs needs to be addressed. By examining mTOR gene-deleted mouse hematopoietic stem cells, which show a loss of quiescence and hyperproliferation, we uncovered the activation of the ERK/MNK/eIF4E/RNA polymerase II/c-Myc axis as an adaptive mechanism to mTOR loss that results in increased chromatin accessibility and activated global gene expression, allowing the cells to hyperproliferate. The work also implicates a potential strategy for overcoming evasive resistance in mTOR-targeted therapies for leukemia.