Therapeutic implications of intra-tumor heterogeneity are still undefined. In this study we report a genetic and functional analysis aimed at defining the mechanisms of chemoresistance in a 43-year old woman affected by stage IVB Burkitt lymphoma with bulky abdominal masses and peritoneal effusion. The patient, despite a transient initial response to chemotherapy with reduction of the bulky masses, rapidly progressed and died of her disease. Targeted TP53 sequencing found that the bulky mass was wild-type whereas peritoneal fluid cells harbored a R282W mutation. Functional studies on TP53 mutant cells demonstrated an impaired p53-mediated response, resistance to ex vivo doxorubicin administration, overexpression of DNA damage response (DDR) activation markers and high sensitivity to pharmacologic DDR inhibition. These findings suggest that intra-tumor heterogeneity for TP53 mutational status may occur in MYC-driven cancers, and that DDR inhibitors could be effective in targeting hidden TP53 mutant clones in tumors characterized by genomic instability and prone to intra-tumor heterogeneity.

Therapeutic implications of intratumor heterogeneity for TP53 mutational status in Burkitt lymphoma

DERENZINI, ENRICO;IACOBUCCI, ILARIA;AGOSTINELLI, CLAUDIO;IMBROGNO, ENRICA;Casadei, Beatrice;FERRARI, ANNA;GHELLI LUSERNA DI RORÀ, ANDREA;MARTINELLI, GIOVANNI;PILERI, STEFANO;ZINZANI, PIER LUIGI
2015

Abstract

Therapeutic implications of intra-tumor heterogeneity are still undefined. In this study we report a genetic and functional analysis aimed at defining the mechanisms of chemoresistance in a 43-year old woman affected by stage IVB Burkitt lymphoma with bulky abdominal masses and peritoneal effusion. The patient, despite a transient initial response to chemotherapy with reduction of the bulky masses, rapidly progressed and died of her disease. Targeted TP53 sequencing found that the bulky mass was wild-type whereas peritoneal fluid cells harbored a R282W mutation. Functional studies on TP53 mutant cells demonstrated an impaired p53-mediated response, resistance to ex vivo doxorubicin administration, overexpression of DNA damage response (DDR) activation markers and high sensitivity to pharmacologic DDR inhibition. These findings suggest that intra-tumor heterogeneity for TP53 mutational status may occur in MYC-driven cancers, and that DDR inhibitors could be effective in targeting hidden TP53 mutant clones in tumors characterized by genomic instability and prone to intra-tumor heterogeneity.
Derenzini, Enrico; Iacobucci, Ilaria; Agostinelli, Claudio; Imbrogno, Enrica; Storlazzi, Clelia Tiziana; L`abbate, Alberto; Casadei, Beatrice; Ferrari, Anna; Ghelli Luserna Di Rorà, Andrea; Martinelli, Giovanni; Pileri, Stefano; Zinzani, Pier Luigi
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/545381
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