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Abstract Disease recurrence characterized by drug resistance remains a major hurdle to the successful cancer treatment. Long noncoding RNAs (lncRNAs) and RNA N⁶-methyladenosine (m6A) have been linked to cancer recurrence. However, if and how lncRNAs and m6A coordinately determine drug resistance in tyrosine kinase (TK) -driven cancers are still unclear. We hypothesize that upon exposure to TK inhibitors (TKI), the dynamic m6A methylation epitransciptomically allows a set of proliferation/anti-apoptosis-relevant lncRNAs bearing m6A motifs to be rapidly upregulated, thus facilitating a subpopulation of cancer cells to evade TKI killing. By performing transcriptomic and epitransciptomic profiling in long-term TKI (nilotinib) -deprived leukemia resistant cells, we show that many differentially expressed lncRNAs enrich m6A, and more lncRNAs tend to have higher m6A content in resistant cells. We further demonstrate a broad clinical relevance of our findings, showing that upregulation of specific top-ranked lncRNAs (e. g. , SENCR, PROX1-AS1, LN892) in TKI-resistant cell lines also occurs in leukemia patients at the diagnostic stage, blast crisis phase or in those not-responding to TKI treatment compared to chronic phase or TKI responders, respectively. Some of the upregulated lncRNAs in leukemia patients pre- and post-TKI treatment predict unfavorable outcomes and are associated with shorter survival duration. Through proliferative and clonogenic assays, we demonstrate that knockdown of SENCR, PROX1-AS1 or LN892 impairs resistant cell growth and renders resistant cells sensitive to nilotinib-induced cell death. We further found that this lncRNA upregulation is attributed to FTO-dependent m6A hypomethylation that stabilizes lncRNA transcripts. Using ectopic expression or genetic/pharmacological inhibition, we demonstrate that lncRNA upregulation empowers resistant cell growth through an activated PI3K signaling as supported by overexpression of PI3K signaling mediators (e. g. , ITGA2, F2R, COL6A1). Treatment with PI3K inhibitor alpelisib sensitizes TKI-resistant cells to TKI-induced cell death and reduces leukemia burden in mice via downregulation of F2R, ITGA2, and COL6A1. In conclusion, our findings add a new layer to the complexity of mechanisms regulating leukemia cell fate under TKI selection and raise the possibility that the m6A-regulated lncRNAs represents a new non-genetic factor to affect the development and maintenance of TKI resistance; our discoveries identify a promising therapeutic target, the m6A-lncRNAs axis, for specifically the most challenging patient subpopulations who are TKI non-responders/relapsed but do not carry the acquired mutations on top of BCR/ABL; our results also uncover a strong predictor, m6A-regulated lncRNA-PI3K axis, for poorer prognosis and failure in drug response which might be a pan-cancer mechanism. Citation Format: Yanhong Tan, Changli Zhou, Sicheng Bian, Wencke Walter, Jiuxia Pang, Tao Cheng, Gang Huang, Gregor Hoermann, William Tse, Shujun Liu. The N6-methyladenine-long noncoding RNA axis promotes drug resistance through PI3k signaling in leukemia abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2008.
Tan et al. (Fri,) studied this question.