Early Mechanisms of Chemoresistance in Retinoblastoma.

Abstract

Retinoblastoma is the most common eye cancer in children and is fatal if left untreated. Over the past three decades, chemotherapy has become the mainstay of eye-sparing treatment. Nevertheless, chemoresistance continues to represent a major challenge leading to ocular and systemic toxicity, vision loss, and treatment failure. Unfortunately, the mechanisms leading to chemoresistance remain incompletely understood. Here, we engineered low-passage human retinoblastoma cells to study the early molecular mechanisms leading to resistance to carboplatin, one of the most widely used agents for treating retinoblastoma. Using single-cell next-generation RNA sequencing (scRNA-seq) and single-cell barcoding technologies, we found that carboplatin induced rapid transcriptomic reprogramming associated with the upregulation of PI3K-AKT pathway targets, including ABC transporters and metabolic regulators. Several of these targets are amenable to pharmacologic inhibition, which may reduce the emergence of chemoresistance. We provide evidence to support this hypothesis using a third-generation inhibitor of the ABCB1 transporter.

• Authors: Michelle G Zhang, Jeffim N Kuznetsoff, Dawn A Owens, Ryan A Gallo, Karthik Kalahasty, Anthony M Cruz, Stefan Kurtenbach, Zelia M Correa, Daniel Pelaez, J William Harbour
• Journal: Cancers (Cancers (Basel)) Vol. 14 Issue 19 (Oct 10 2022) ISSN: 2072-6694 [Print] Switzerland
• PMID: 36230889 (Publication Type: Journal Article)