Abstract 1981: Pan-cancer pathways gene expression profiling in mantle cell lymphoma reveals upregulation of DNA damage repair genes in ibrutinib-resistant tumor
Authors: Ahmed Makhdum , Lorence Elizabeth , Guo Hui , Huang Shengjian , Zhang Victoria , Zhang Hui , Zhang Liang , Nomie Krystle , Wang Michael 
Published: August 2018

Introduction Mantle cell lymphoma (MCL) accounts for 7% of all non-Hodgkin lymphoma cases and is an incurable subtype of B-cell lymphoma. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton's tyrosine kinase (BTK), was approved by the FDA in 2013 for relapsed-refractory MCL with an overall response rate of 68%. Unfortunately, resistance to ibrutinib inevitably develops and once patients relapse after ibrutinib treatment, the 1-year survival rate is only 22%, and median survival is only 8 months. If the response to ibrutinib can be predicted by genetic biomarkers, the ability to personalize therapy in the clinic would greatly benefit; therefore, we aimed to identify the gene expression profile associated with ibrutinib resistance in clinical samples.

Methods We used clinical samples (N=16) collected from relapsed MCL patients to extract RNA, and the RNA samples were used to conduct gene expression profiling of 770 genes using Nanostring® Pan Cancer Pathways Panel in the nCounter® system (Seattle, WA). Gene expression profiling analysis was adjusted for technical and biological covariates such as binding density and sample type. We adjusted the analysis for multiples statistical comparisons using the Benjamini-Yekutieli method.

Results Of the 16 clinical samples, 5 (31%) were resistant to ibrutinib as identified in clinical annotations. In univariate analysis, binding density was significantly higher in ibrutinib-resistant samples compared with the sensitive samples (P-value &lt;0.001). After adjusting for binding density and sample type, we reported top 20 genes differentially expressed in the resistant samples compared with the ibrutinib-sensitive samples. SMC1B, FGFR1, CDK2, PCNA, RFC4 are among the top 20 differentially expressed genes and, belong to cell cycle control, DNA damage repair, MAPK and PI3K pathways. The pathway scores revealed that the ibrutnib-resistant samples had higher expression of DNA damage repair genes but lower expression of apoptotic genes, which is in contrast with the ibrutinib sensitive samples. Additionally, ibrutinib-resistant samples had significantly higher expressions of PI3K and NOTCH pathway genes and lower expression of JAK-STAT pathway genes as compared with the sensitive samples. These findings of differential expression of apoptosis and DNA repair genes in ibrutinib-resistant and sensitive samples were independently validated by RNA-seq experiments, presented elsewhere.

Conclusions In ibrutinib-resistant MCL samples, the ability to increase DNA damage repair and relative lower expression of apoptotic genes may explain the resistance mechanism. MCL cells may be vulnerable to therapeutic intervention targeting DNA damage repair pathways.

Citation Format: Makhdum Ahmed, Elizabeth Lorence, Hui Guo, Shengjian Huang, Victoria Zhang, Hui Zhang, Liang Zhang, Krystle Nomie, Michael Wang. Pan-cancer pathways gene expression profiling in mantle cell lymphoma reveals upregulation of DNA damage repair genes in ibrutinib-resistant tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1981.