LncRNA H19 downregulation confers erlotinib resistance through upregulation of PKM2 and phosphorylation of AKT in EGFR-mutant lung cancers

Cancer Lett. 2020 Aug 28;486:58-70. doi: 10.1016/j.canlet.2020.05.009. Epub 2020 May 18.

Abstract

First-generation EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib have significant activity in NSCLC patients with activating EGFR mutations. However, EGFR-TKI resistance inevitably occurs after approximately 12 months of treatment. Acquired mechanisms of resistance, other than secondary mutations in EGFR (T790 M) which account for 50-60%, are less well understood. Here, we identified lncRNA H19 as a significantly downregulated lncRNA in vitro models and clinical specimens with acquired EGFR-TKI resistance, H19 knockdown or overexpression conferred resistance or sensitivity, respectively, both in vitro and in vivo models. H19 downregulation contributed to erlotinib resistance through interaction and upregulation of PKM2, which enhanced the phosphorylation of AKT. AKT inhibitors restored the sensitivity of erlotinib-resistant cells to erlotinib. In EGFR-mutant patients treated with EGFR-TKIs, low H19 levels were associated with a shorter progression-free survival (PFS) (P = 0.021). These findings revealed a novel mechanism of low-level H19 in the regulation of erlotinib resistance in EGFR-mutant lung cancers. Combination of AKT inhibitors and EGFR-TKIs could be a rational therapeutic approach for some subgroups of EGFR-mutant lung cancer patients.

Keywords: AKT inhibitor; Acquired EGFR-TKI resistance; H19 expression; Non-small-cell lung cancer; PKM2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Carrier Proteins / physiology*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics*
  • Erlotinib Hydrochloride / pharmacology*
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Male
  • Membrane Proteins / physiology*
  • Mice
  • Middle Aged
  • Mutation*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Long Noncoding / physiology*
  • Thyroid Hormones / physiology*
  • Up-Regulation

Substances

  • Carrier Proteins
  • H19 long non-coding RNA
  • Membrane Proteins
  • RNA, Long Noncoding
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt