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 / E. Derenzini, I. Iacobucci, C. Agostinelli, E. Imbrogno, C.T. Storlazzi, A. L'Abbate, B. Casadei, A. Ferrari, A.G.L. Di Rora, G. Martinelli, S. Pileri, P.L. Zinzani. - In: EXPERIMENTAL HEMATOLOGY & ONCOLOGY. - ISSN 2162-3619. - 4:1(2015), pp. 24.1-24.5.
Therapeutic implications of intratumor heterogeneity for TP53 mutational status in Burkitt lymphoma
E. Derenzini;
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.File | Dimensione | Formato | |
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