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Review
. 2024 Jul 11;15(7):906.
doi: 10.3390/genes15070906.

The Potential Links between lncRNAs and Drug Tolerance in Lung Adenocarcinoma

William J H Davis  1   2 , Catherine J Drummond  1   2 , Sarah Diermeier  3   4 , Glen Reid  1   2
Affiliations
Review

The Potential Links between lncRNAs and Drug Tolerance in Lung Adenocarcinoma

William J H Davis et al. Genes (Basel). .

Abstract

Lung cancer patients treated with targeted therapies frequently respond well but invariably relapse due to the development of drug resistance. Drug resistance is in part mediated by a subset of cancer cells termed "drug-tolerant persisters" (DTPs), which enter a dormant, slow-cycling state that enables them to survive drug exposure. DTPs also exhibit stem cell-like characteristics, broad epigenetic reprogramming, altered metabolism, and a mutagenic phenotype mediated by adaptive mutability. While several studies have characterised the transcriptional changes that lead to the altered phenotypes exhibited in DTPs, these studies have focused predominantly on protein coding changes. As long non-coding RNAs (lncRNAs) are also implicated in the phenotypes altered in DTPs, it is likely that they play a role in the biology of drug tolerance. In this review, we outline how lncRNAs may contribute to the key characteristics of DTPs, their potential roles in tolerance to targeted therapies, and the emergence of genetic resistance in lung adenocarcinoma.

Keywords: acquired drug resistance; drug tolerance; lncRNA; lung adenocarcinoma; targeted therapy.

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Conflict of interest statement

Author Sarah Diermeier is the founder and a shareholder of the company Amaroq Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Drug-tolerant persisters lead to drug resistance and relapse. Adaptive cell responses lead to resistance to targeted therapies via the emergence of drug-tolerant persisters (DTPs). DTPs enter a reversible dormant state that allows them to survive treatment [3] and become a reservoir for the development of resistance-conferring mutation, which leads to stable genetic resistance [7].
Figure 2
Figure 2
Key features of drug tolerance. Drug tolerant persisters (DTPs) exhibit several characteristic features including metabolic and epigenetic reprogramming, cell cycle arrest, and stem-cell-like and mutagenic phenotypes [13]. Arrows represent up or downregulation of the pathways indicated.
Figure 3
Figure 3
Non-Coding RNA Regulation of HOX Loci. HOX loci are thought to be extensively regulated by lncRNAs, including the lncRNAs HOTAIR and HOTTIP [47]. HOX genes play an important role in development and cell plasticity [48], which are phenotypes widely seen in drug tolerance in LUAD, and thus may be important players in this response. HOX genes are arranged in 4 clusters in humans, with each cluster containing several HOX genes (numbers shown). HOX genes are expressed spatially during embryogenesis, with green and yellow colours representing HOX genes expressed anteriorly and centrally, and red representing HOX genes expressed posteriorly in humans.
Figure 4
Figure 4
Potential roles of MALAT1 and NEAT1 in the DTP phenotype. Both MALAT1 and NEAT1 are architectural lncRNAs involved in nuclear organisation and regulation [103,104]. They also regulate protein, chromatin, RNA, and DNA independently of their architectural roles. These functions include the regulation of several characteristics of DTPs, including but not limited to chromatin remodelling, stem cell factor regulation, de-differentiation, and DNA damage responses.
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