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DOI	10.1073/pnas.2024055118
	Acquired resistance to PRMT5 inhibition induces concomitant collateral sensitivity to paclitaxel
	Mueller H.S.; Fowler C.E.; Dalin S.; Moiso E.; Udomlumleart T.; Garg S.; Hemann M.T.; Lees J.A.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:34
英文摘要	Epigenetic regulators play key roles in cancer and are increasingly being targeted for treatment. However, for many, little is known about mechanisms of resistance to the inhibition of these regulators. We have generated a model of resistance to inhibitors of protein arginine methyltransferase 5 (PRMT5). This study was conducted in KrasG12D;Tp53-null lung adenocarcinoma (LUAD) cell lines. Resistance to PRMT5 inhibitors (PRMT5i) arose rapidly, and barcoding experiments showed that this resulted from a drug-induced transcriptional state switch, not selection of a preexisting population. This resistant state is both stable and conserved across variants arising from distinct LUAD lines. Moreover, it brought with it vulnerabilities to other chemotherapeutics, especially the taxane paclitaxel. This paclitaxel sensitivity depended on the presence of stathmin 2 (STMN2), a microtubule regulator that is specifically expressed in the resistant state. Remarkably, STMN2 was also essential for resistance to PRMT5 inhibition. Thus, a single gene is required for both acquisition of resistance to PRMT5i and collateral sensitivity to paclitaxel in our LUAD cells. Accordingly, the combination of PRMT5i and paclitaxel yielded potent and synergistic killing of the murine LUAD cells. Importantly, the synergy between PRMT5i and paclitaxel also extended to human cancer cell lines. Finally, analysis of The Cancer Genome Atlas patient data showed that high STMN2 levels correlate with complete regression of tumors in response to taxane treatment. Collectively, this study reveals a recurring mechanism of PRMT5i resistance in LUAD and identifies collateral sensitivities that have potential clinical relevance. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Collateral sensitivity; PRMT5i resistance; STMN2
语种	英语
scopus关键词	antineoplastic agent; paclitaxel; Prmt5 protein, mouse; protein arginine methyltransferase; stathmin; Stmn2 protein, mouse; animal; cell proliferation; drug potentiation; drug resistance; gene expression regulation; gene knockdown; genetic epigenesis; genetics; human; lung adenocarcinoma; lung tumor; metabolism; mouse; mutation; tumor cell line; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Lung Neoplasms; Mice; Mutation; Paclitaxel; Protein-Arginine N-Methyltransferases; Stathmin
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251042
作者单位	The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, United States
推荐引用方式 GB/T 7714	Mueller H.S.,Fowler C.E.,Dalin S.,et al. Acquired resistance to PRMT5 inhibition induces concomitant collateral sensitivity to paclitaxel[J],2021,118(34).
APA	Mueller H.S..,Fowler C.E..,Dalin S..,Moiso E..,Udomlumleart T..,...&Lees J.A..(2021).Acquired resistance to PRMT5 inhibition induces concomitant collateral sensitivity to paclitaxel.Proceedings of the National Academy of Sciences of the United States of America,118(34).
MLA	Mueller H.S.,et al."Acquired resistance to PRMT5 inhibition induces concomitant collateral sensitivity to paclitaxel".Proceedings of the National Academy of Sciences of the United States of America 118.34(2021).