Hypoxia-inducible APCDD1L-AS1 promotes osimertinib resistance by stabilising DLST to drive tricarboxylic acid cycle in lung adenocarcinoma

J Exp Clin Cancer Res. 2025 Jul 9;44(1):197. doi: 10.1186/s13046-025-03462-z.

Abstract

Acquired resistance is unavoidable in lung adenocarcinoma (LUAD) treated with osimertinib, however, the underlying mechanisms remain largely unknown. Here, we report that the long non-coding RNA (lncRNA) APCDD1L-AS1 is upregulated in osimertinib-resistant LUAD tissues and cells and is associated with short survival of osimertinib-resistant LUAD patients. Our data showed that APCDD1L-AS1 upregulation is an independent risk factor for overall survival in patients with osimertinib-resistant LUAD. APCDD1L-AS1 knockdown enhanced osimertinib sensitivity both in vitro and in vivo, whereas APCDD1L-AS1 overexpression promoted osimertinib resistance. Mechanistically, APCDD1L-AS1 accelerates the tricarboxylic acid (TCA) cycle by forming complexes and maintaining the stability of dihydrolipoamide S-succinyltransferase (DLST), which inhibits the ubiquitination and degradation of DLST. Moreover, we demonstrate that hypoxia-inducible factor (HIF)-1α transcriptionally activates APCDD1L-AS1 by binding to the APCDD1L-AS1 promoter region under hypoxic conditions. Overall, our data confirm that APCDD1L-AS1 is upregulated by hypoxia-induced HIF-1α, which drives the TCA cycle by stabilising DLST to further promote osimertinib resistance in LUAD. Our findings provide new insights into the role of HIF-1α/APCDD1L-AS1/DLST axis-related reprogramming of hypoxia and the TCA balance in conferring osimertinib resistance in LUAD and confirm the therapeutic potential for targeting the APCDD1L-AS1.

Keywords: Hypoxia; Long non-coding RNAs; Lung adenocarcinoma; Osimertinib-resistant; Tricarboxylic acid cycle.

MeSH terms

  • Acrylamides* / pharmacology
  • Acrylamides* / therapeutic use
  • Adenocarcinoma of Lung* / drug therapy
  • Adenocarcinoma of Lung* / genetics
  • Adenocarcinoma of Lung* / metabolism
  • Adenocarcinoma of Lung* / pathology
  • Aniline Compounds* / pharmacology
  • Aniline Compounds* / therapeutic use
  • Animals
  • Cell Line, Tumor
  • Citric Acid Cycle*
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Indoles
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Male
  • Mice
  • Pyrimidines
  • RNA, Long Noncoding* / genetics
  • Xenograft Model Antitumor Assays

Substances

  • osimertinib
  • Acrylamides
  • Aniline Compounds
  • RNA, Long Noncoding
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • HIF1A protein, human
  • Indoles
  • Pyrimidines