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.
Highlights
Proviral Integration in Moloney murine leukemia virus (PIM) kinases are a family of serine-threonine kinases that play a role in hepatoblastoma tumorigenicity[20]
We demonstrated that PIM inhibition increased sensitivity to cisplatin in the cisplatin-resistant cells, significantly inhibiting proliferation, enhancing cisplatin-induced apoptosis, and reducing the stem cell‐like cancer cell (SCLCC) phenotype that contributes to cisplatin resistance
Using Quantitative real-time PCR (qPCR), we found that the abundance of mRNA of the cancer stem cell marker Aldehyde dehydrogenase 1A3 (ALDH1A3) and the Notch pathway genes ( NOTCH1 and NOTCH3) was upregulated in the cisplatin-resistant compared to the cisplatin-naïve hepatoblastoma cells (p < 0.05, Supplementary Info Figure S2)
Summary
Proviral Integration in Moloney murine leukemia virus (PIM) kinases are a family of serine-threonine kinases that play a role in hepatoblastoma tumorigenicity[20]. PIM inhibition combined with cisplatin synergistically decreased tumor growth in vivo leading us to believe that PIM3 plays a role in mediating chemoresistance to cisplatin hepatoblastoma by maintaining the SCLCC phenotype. We demonstrated that PIM inhibition increased sensitivity to cisplatin in the cisplatin-resistant cells, significantly inhibiting proliferation, enhancing cisplatin-induced apoptosis, and reducing the SCLCC phenotype that contributes to cisplatin resistance. These data provide evidence for the role of PIM kinases in chemoresistance in hepatoblastoma and propose PIM inhibition as a strategy to potentially overcome cisplatin resistance by targeting the SCLCC phenotype
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