title: TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma.
abstract: In tumours that harbour wild-type p53, p53 protein function is frequently disabled by the mouse double minute 2 protein (MDM2, or HDM2 in humans). Multiple HDM2 antagonists are currently in clinical development. Preclinical data indicate that TP53 mutations are a possible mechanism of acquired resistance to HDM2 inhibition; however, this resistance mechanism has not been reported in patients. Utilizing liquid biopsies, here we demonstrate that TP53 mutations appear in circulating cell-free DNA obtained from patients with de-differentiated liposarcoma being treated with an inhibitor of the HDM2-p53 interaction (SAR405838). TP53 mutation burden increases over time and correlates with change in tumour size, likely representing selection of TP53 mutant clones resistant to HDM2 inhibition. These results provide the first clinical demonstration of the emergence of TP53 mutations in response to an HDM2 antagonist and have significant implications for the clinical development of this class of molecules.
authors: Sanofi Oncology, Cambridge, Massachusetts 02139, USA.
authors: Joonil
authors: J
authors: Jung
authors: Sanofi Oncology, Cambridge, Massachusetts 02139, USA.
authors: Joon Sang
authors: JS
authors: Lee
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors: Mark A
authors: MA
authors: Dickson
authors: Columbia University Medical Center, New York, New York 10032, USA.
authors: Gary K
authors: GK
authors: Schwartz
authors: Department of Cancer Medicine, Gustave Roussy, Villejuif 94800, France.
authors: Axel
authors: A
authors: Le Cesne
authors: Department of Cancer Medicine, Gustave Roussy, Villejuif 94800, France.
authors: Andrea
authors: A
authors: Varga
authors: Department of Cancer Medicine, Gustave Roussy, Villejuif 94800, France.
authors: Rastilav
authors: R
authors: Bahleda
authors: Center for Sarcoma and Bone Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Andrew J
authors: AJ
authors: Wagner
authors: Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors: Edwin
authors: E
authors: Choy
authors: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam 3015 CE, The Netherlands.
authors: Maja J
authors: MJ
authors: de Jonge
authors: Sanofi Oncology, Cambridge, Massachusetts 02139, USA.
authors: Madelyn
authors: M
authors: Light
authors: Sanofi Oncology, Cambridge, Massachusetts 02139, USA.
authors: Steve
authors: S
authors: Rowley
authors: Sanofi Oncology, Vitry-sur-Seine 94400, France.
authors: Sandrine
authors: S
authors: Macé
authors: Sanofi Oncology, Cambridge, Massachusetts 02139, USA.
authors: James
authors: J
authors: Watters
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001706:Biopsy; D002454:Cell Differentiation; D000074141:Circulating Tumor DNA / Q000235:genetics / Q000302:isolation & purification; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008080:Liposarcoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066066:Response Evaluation Criteria in Solid Tumors; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000074141:Circulating Tumor DNA; D007211:Indoles; D013141:Spiro Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000593797:SAR405838; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2