HER2-positive breast-cancer cell lines are sensitive to KDM5 inhibition: definition of a gene-expression model for the selection of sensitive cases

• Published in: Oncogene Vol. 38; no. 15; pp. 2675 - 2689
• Main Authors: Paroni, Gabriela, Bolis, Marco, Zanetti, Adriana, Ubezio, Paolo, Helin, Kristian, Staller, Peter, Gerlach, Lars Ole, Fratelli, Maddalena, Neve, Richard M., Terao, Mineko, Garattini, Enrico
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2019; Nature Publishing Group
• Subjects: 38; 38/91; 631/67/1347; 692/53/2423; Apoptosis; Breast cancer; Cancer cells; Cancer genetics; Care and treatment; Cell Biology; Chemotherapy; ErbB-2 protein; Estrogen receptors; Gene expression; Genes; Genetic aspects; Human Genetics; Internal Medicine; Lapatinib; Medicine; Medicine & Public Health; Methylation; Monoclonal antibodies; Oncology; Proteins; Ribonucleic acid; RNA; Targeted cancer therapy; Trastuzumab; Tumor cell lines; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0620-6

Targeting of histone methylation has therapeutic potential in oncology. Here, we provide proof-of-principle that pharmacological inhibition of KDM5 histone-demethylases is a new strategy for the personalized treatment of HER2
+
breast cancer. The anti-proliferative effects of the prototype of a new class of selective KDM5-inhibitors (
KDM5-inh1
) are evaluated in 40 cell lines, recapitulating the heterogeneity of breast cancer. This analysis demonstrates that HER2
+
cells are particularly sensitive to KDM5 inhibition. The results are confirmed in an appropriate in vivo model with a close structural analog (
KDM5-inh1A
). RNA-seq data obtained in HER2
+
BT-474
cells exposed to
KDM5-Inh1
indicate that the compound alters expression of numerous genes downstream of the
ERBB2
gene-product, HER2. In selected HER2-positive breast-cancer cells, we demonstrate synergistic interactions between
KDM5-inh1
and HER2-targeting agents (trastuzumab and lapatinib). In addition, HER2
+
cell lines with innate and acquired resistance to trastuzumab show sensitivity to
KDM5-inh1
. The levels of KDM5A/B/C proteins, which are selectively targeted by the agent, have no significant association with
KDM5-inh1
responsiveness across our panel of breast-cancer cell lines, suggesting the existence of other determinants of sensitivity. Using RNA-seq data of the breast-cancer cell lines we generate a gene-expression model that is a robust predictor of
KDM5-inh1
sensitivity. In a test set of breast cancers, this model predicts sensitivity to the compound in a large fraction of HER2
+
tumors. In conclusion, KDM5 inhibition has potential in the treatment of HER2
+
breast cancer and our gene-expression model can be developed into a diagnostic tool for the selection of patients.