Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide-chlorambucil conjugate.

Abstract

Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3-RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC-TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3-RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3-RCC cells, PRCC-TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC-TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil-polyamide conjugate (Chb) to target PRCC-TFE3-dependent transcription, and identified Chb16 as a PRCC-TFE3-dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient-derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3-RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3-RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3-RCC.

• Authors: Shintaro Funasaki, Sally Mehanna, Wenjuan Ma, Hidekazu Nishizawa, Yasuhiko Kamikubo, Hiroshi Sugiyama, Shuji Ikeda, Takanobu Motoshima, Hisashi Hasumi, W Marston Linehan, Laura S Schmidt, Chris Ricketts, Toshio Suda, Yuichi Oike, Tomomi Kamba, Masaya Baba
• Journal: Cancer science (Cancer Sci) Vol. 113 Issue 7 Pg. 2352-2367 (Jul 2022) ISSN: 1349-7006 [Electronic] England
• PMID: 35396773 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Nylons
• Chlorambucil

Topics

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (genetics, metabolism)
• Carcinoma, Renal Cell (drug therapy, genetics, metabolism)
• Chlorambucil (pharmacology)
• Chromosomes, Human, X
• Drug Resistance, Neoplasm (genetics)
• Humans
• Kidney Neoplasms (drug therapy, genetics, metabolism)
• Nylons
• Translocation, Genetic