Abstract P3-06-19: MUC17 and PCNX1 as mediators of chemotherapy response in breast cancer

Abstract

Breast cancer is a heterogeneous disease and accumulating evidence suggests that treatment failure may be driven by intra-tumour heterogeneity (ITH). Utilising the current protocol for neoadjuvant (pre-surgery) chemotherapy (NAC) provides the opportunity to study molecular genetic changes between pre- and post-therapy by assessing pre-therapy biopsies and post-therapy surgical resections. Whole exome sequencing was performed on matched pre- and post-treatment cancer cells from 6 patients with oestrogen receptor positive breast cancers that showed partial responses to the chemotherapeutic epirubicin. Data analysis was performed to determine differences in genetic aberrations between pre- and post-NAC, and in particular to identify evidence of consistent selection by therapy of aberrations that therefore may define chemotherapy resistance or sensitivity. There were extensive differences in the range of genetic aberrations between pre- and post-NAC. 48 genes were identified for further study based on evidence of mutations conferring a selective advantage or disadvantage during chemotherapeutic response. The relevance of these was screened using siRNA knock-down and assessment of response to chemotherapeutic drug using cell viability assays in vitro. Two genes were taken forward. Potential loss-of-function mutations in the MUC17 gene were selected against during therapy in patients, and in accordance with this MUC17 knock-down was associated with increased sensitivity in vitro. Potential loss-of-function mutations in the PCNX1 gene were selected for during therapy in patients, and in accordance with this PCNX1 knock-down was associated with resistance. Further work was done to investigate mechanisms by which these genes modify cellular chemotherapy response, by examining drug loading and ABC transporter expression levels. Data indicate that both genes impact on drug loading, potentially through modulating ABC transporter activities. Using available transcriptomic datasets, expression of neither gene correlated with breast cancer outcomes in mixed cohorts that received a wide-range of therapies, however, analysis of correlations between protein expression and outcomes specifically after chemotherapy are on-going. We conclude that MUC17 and PCNX1 are potential markers of response to chemotherapy in breast cancer, and therapeutic modulation of their activities could enhance chemotherapy responses. Citation Format: Al Amri W, Verghese E, Stead L, Hanby A, Sharma N, Hughes T. MUC17 and PCNX1 as mediators of chemotherapy response in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-19.