Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma.

TitleCell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma.
Publication TypeJournal Article
Year of Publication2014
AuthorsChiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P, Mathew S, Vijay P, Eng K, Ali S, Johnson A, Chang B, Ely S, Elemento O, Mason CE, Leonard JP, Chen-Kiang S
JournalCancer Discov
Date Published2014 Sep
KeywordsAgammaglobulinaemia Tyrosine Kinase, Amino Acid Substitution, Antineoplastic Agents, Cell Cycle, Cell Line, Tumor, DNA Mutational Analysis, Drug Resistance, Neoplasm, Drug Synergism, Enzyme Activation, Genomics, Humans, Lymphoma, Mantle-Cell, Mutation, Neoplasm Recurrence, Local, NF-kappa B, Nitrates, Phosphoinositide-3 Kinase Inhibitors, Polyethylene Glycols, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcr, Pyrazoles, Pyrimidines, Signal Transduction, Treatment Outcome

UNLABELLED: 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.

SIGNIFICANCE: 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.

Alternate JournalCancer Discov
PubMed ID25082755
PubMed Central IDPMC4155003
Grant ListR21 CA176362 / CA / NCI NIH HHS / United States
T32 GM083937 / GM / NIGMS NIH HHS / United States