title: Heterogeneous Mechanisms of Secondary Resistance and Clonal Selection in Sarcoma during Treatment with Nutlin.
abstract: Nutlin inhibits TP53-MDM2 interaction and is under investigation in soft-tissue sarcomas (STS) and other malignancies. Molecular mechanisms of secondary resistance to nutlin in STS are unknown. We performed whole-transcriptome sequencing (RNA-seq) on three pretreatment and secondary resistant STS cell lines selected based on their high primary sensitivity to nutlin. Our data identified a subset of cancer gene mutations and ploidy variations that were positively selected following treatment, including TP53 mutations in 2 out of 3 resistant cell lines. Further, secondary resistance to nutlin was associated with deregulation of apoptosis-related genes and marked productive autophagy, the inhibition of which resulted in significant restoration of nutlin-induced cell death. Collectively, our findings argue that secondary resistance to nutlin in STS involved heterogeneous mechanisms resulting from clonal evolution and several biological pathways. Alternative dosing regimens and combination with other targeted agents are needed to achieve successful development of nutlin in the clinical setting.
authors.affiliation: INSERM U916, Institut Bergonié, Bordeaux, France; Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Laroche
authors.affiliation: INSERM U916, Institut Bergonié, Bordeaux, France; Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Tran-Cong
authors.affiliation: INSERM U916, Institut Bergonié, Bordeaux, France; Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Chaire
authors.affiliation: INSERM U916, Institut Bergonié, Bordeaux, France; Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Lagarde
authors.affiliation: Pathology Department, Institut Bergonié, Bordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hostein
authors.affiliation: Sarcoma Unit, Institut Bergonié, Bordeaux, France; Pathology Department, Institut Bergonié, Bordeaux, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.affiliation: INSERM U916, Institut Bergonié, Bordeaux, France; Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Chibon
authors.affiliation: Sarcoma Unit, Institut Bergonié, Bordeaux, France; Pathology Department, Institut Bergonié, Bordeaux, France.
authors.forename: Agnes
authors.initials: A
authors.lastname: Neuville
authors.affiliation: INSERM U916, Institut Bergonié, Bordeaux, France; Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Tom
authors.initials: T
authors.lastname: Lesluyes
authors.affiliation: INSERM U916, Institut Bergonié, Bordeaux, France; Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Carlo
authors.initials: C
authors.lastname: Lucchesi
authors.affiliation: INSERM U916, Institut Bergonié, Bordeaux, France; Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009154:Mutation; D011003:Ploidies; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D062366:para-Aminobenzoates / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011759:Pyrrolidines; C586849:RG7388; D016159:Tumor Suppressor Protein p53; D062366:para-Aminobenzoates; C029899:imidazole; D051736:Proto-Oncogene Proteins c-mdm2