PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma

Sci Rep. 2021 Mar 16;11(1):5984. doi: 10.1038/s41598-021-85289-0.

Abstract

Despite increasing incidence, treatment for hepatoblastoma has not changed significantly over the past 20 years. Chemotherapeutic strategies continue to rely on cisplatin, as it remains the most active single agent against hepatoblastoma. However, chemoresistance remains a significant challenge with 54-80% of patients developing resistance to chemotherapy after 4-5 cycles of treatment. Stem cell-like cancer cells (SCLCCs) are a subset of cells thought to play a role in chemoresistance and disease recurrence. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia virus (PIM) kinases, specifically PIM3, play a role in hepatoblastoma cell proliferation and tumor growth and maintain the SCLCC phenotype. Here, we describe the development of a cisplatin-resistant hepatoblastoma xenograft model of the human HuH6 cell line and a patient-derived xenograft, COA67. We provide evidence that these cisplatin-resistant cells are enriched for SCLCCs and express PIM3 at higher levels than cisplatin-naïve cells. We demonstrate that PIM inhibition with AZD1208 sensitizes cisplatin-resistant hepatoblastoma cells to cisplatin, enhances cisplatin-mediated apoptosis, and decreases the SCLCC phenotype seen with cisplatin resistance. Together, these findings indicate that PIM inhibition may be a promising adjunct in the treatment of hepatoblastoma to effectively target SCLCCs and potentially decrease chemoresistance and subsequent disease relapse.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Biphenyl Compounds / pharmacology
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Cisplatin / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm* / genetics
  • Enzyme Activation
  • Gene Expression
  • Hepatoblastoma / drug therapy
  • Hepatoblastoma / etiology
  • Hepatoblastoma / metabolism*
  • Hepatoblastoma / pathology
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / etiology
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Mice
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Phenotype
  • Proto-Oncogene Proteins c-pim-1 / genetics
  • Proto-Oncogene Proteins c-pim-1 / metabolism*
  • Thiazolidines / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • AZD1208
  • Antineoplastic Agents
  • Biphenyl Compounds
  • Thiazolidines
  • Proto-Oncogene Proteins c-pim-1
  • proto-oncogene proteins pim
  • Cisplatin