| Autor: |
Marayati R; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Stafman LL; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Williams AP; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Bownes LV; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Quinn CH; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Aye JM; Department of Pediatric Hematology Oncology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Stewart JE; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Yoon KJ; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Anderson JC; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Willey CD; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Beierle EA; Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. South, Lowder Building, Suite 300, Birmingham, AL, 35233, USA. elizabeth.beierle@childrensal.org. |
| Abstrakt: |
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. |
