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

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.