Abstract 897: Elucidating the molecular basis of intrinsic taxane resistance in gastric cancer
Authors: Galletti Giuseppe , Cleveland Kyle , Zhang Chao , Gjyrezi Ada , Matov Alexandre , Betel Doron , Shah Manish A. , Giannakakou Paraskevi 
Published: May 2015

Gastric cancer (GC) is histologically divided into intestinal (INT) and diffuse (DIF) clinical subtypes. Even though these two GC groups are structurally and biologically different, this classification is not used to inform choice of treatment.

The taxanes (i.e., docetaxel and cabazitaxel) are widely used for the treatment of cancer and for GC specifically the TAX-325 study revealed a significantly improved survival when docetaxel (DTX) was added to cisplatin and fluorouracil. Despite this advancement, patients still exhibit intrinsic or acquired resistance to DTX. Yet, the molecular basis of drug resistance remains unknown.

We performed a post-hoc analysis of the TAX-325 study to examine the potential influence of GC subtypes in clinical response to DTX. We classified randomized patients as diffuse or non-diffuse histology and correlated histology with clinical outcomes using a Cox proportional hazards model. Non-diffuse GC showed a significant improvement in overall survival with the addition of DTX (12.1 v 8.8 mo, p=0.002), whereas diffuse histology was not associated with an improvement in survival (8.3 v 8.5 mo, p=0.66). To investigate the molecular mechanism of GC DIF subtype resistance to taxanes, we used a panel of 12 GC cell lines representative of both subtypes (4 intestinal subtype, 8 diffuse subtype). DTX cytotoxicity assays revealed that similarly to what we observed clinically, 5/8 (63%) DIF GC cell lines were resistant (IC50 &gt; 600 nM) to DTX compared to 1/4 (25%) INT GC cell lines. Further functional studies revealed that there was minimal DTX drug-target engagement in the DIF GC cells, as, assessed by confocal microscopy of the microtubule network and tubulin polymerization assays. These results suggested that DTX interaction with its target, microtubule, was impaired in the DIF GC cell lines. To rule out multi-drug resistance (MDR) as potential cause of intrinsic DTX resistance in these cells we performed flow cytometric evaluation of P-glycoprotein and found that all of the DIF GC cell lines were negative. Additionally, drug accumulation studies with C-14 radiolabeled DTX revealed that the drug accumulated intracellularly in all of GC cell lines in our panel.

Next generation sequencing of our panel of untreated or DTX-treated GC cell lines revealed a number of genes/pathways that are differentially expressed in the drug-sensitive versus the resistant cell lines. Gene set enrichment analysis is currently ongoing in order to identify a subset of genes/pathways implicated in intrinsic DTX resistance in GC. These studies will provide novel insights into mechanism of intrinsic drug resistance and will ultimately allow us to design more effective targeted therapies to overcome chemo-resistance and eventually prolong patient survival.

Citation Format: Giuseppe Galletti, Kyle Cleveland, Chao Zhang, Ada Gjyrezi, Alexandre Matov, Doron Betel, Manish A. Shah, Paraskevi Giannakakou. Elucidating the molecular basis of intrinsic taxane resistance in gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 897. doi:10.1158/1538-7445.AM2014-897