title: Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma.
abstract: Despite the unprecedented clinical activity of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib in mantle cell lymphoma (MCL), acquired resistance is common. By longitudinal integrative whole-exome and whole-transcriptome sequencing and targeted sequencing, we identified the first relapse-specific C481S mutation at the ibrutinib binding site of BTK in MCL cells at progression following a durable response. This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance. Through synergistic induction of PIK3IP1 and inhibition of PI3K-AKT activation, prolonged early G1 arrest induced by PD 0332991 (palbociclib) inhibition of CDK4 sensitized resistant lymphoma cells to ibrutinib killing when BTK was unmutated, and to PI3K inhibitors independent of C481S mutation. These data identify a genomic basis for acquired ibrutinib resistance in MCL and suggest a strategy to override both primary and acquired ibrutinib resistance.
  
  
  CONCLUSIONS
  We have discovered the first relapse-specific BTK mutation in patients with MCL with acquired resistance, but not primary resistance, to ibrutinib, and demonstrated a rationale for targeting the proliferative resistant MCL cells by inhibiting CDK4 and the cell cycle in combination with ibrutinib in the presence of BTK(WT) or a PI3K inhibitor independent of BTK mutation. As drug resistance remains a major challenge and CDK4 and PI3K are dysregulated at a high frequency in human cancers, targeting CDK4 in genome-based combination therapy represents a novel approach to lymphoma and cancer therapy. Cancer Discov; 4(9); 1022-35. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 973.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Chiron
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Di Liberto
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Martin
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Xiangao
authors.initials: X
authors.lastname: Huang
authors.affiliation: Willamette Valley Cancer Institute and Research Center/US Oncology Research, Springfield, Oregon.
authors.forename: Jeff
authors.initials: J
authors.lastname: Sharman
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York. Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Pedro
authors.initials: P
authors.lastname: Blecua
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Susan
authors.initials: S
authors.lastname: Mathew
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York. Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Vijay
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York. Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Ken
authors.initials: K
authors.lastname: Eng
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Siraj
authors.initials: S
authors.lastname: Ali
authors.affiliation: Ohio State University, Columbus, Ohio.
authors.forename: Amy
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Pharmacyclics, Sunnyvale, California.
authors.forename: Betty
authors.initials: B
authors.lastname: Chang
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Scott
authors.initials: S
authors.lastname: Ely
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York. Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York. Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mason
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York. Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, New York. sckiang@med.cornell.edu.
authors.forename: Selina
authors.initials: S
authors.lastname: Chen-Kiang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D004789:Enzyme Activation; D023281:Genomics; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009364:Neoplasm Recurrence, Local; D009566:Nitrates / Q000494:pharmacology / Q000627:therapeutic use; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051562:Proto-Oncogene Proteins c-bcr / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D009566:Nitrates; C514522:PG1 compound; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011092:Polyethylene Glycols; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D051057:Proto-Oncogene Proteins c-akt; D051562:Proto-Oncogene Proteins c-bcr; D000225:Adenine
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