Abstract 5159: Isoform specific expression of cadherin10 is associated with progression and drug resistance in non-small cell lung cancer

Abstract

Abstract Lung cancer is the leading cause of cancer related death worldwide accounting for 1.69 million of total 8.8 million cancer deaths in 2015 alone. Nearly 85% of all lung cancer cases are classified as non-small cell lung cancer (NSCLC) with a 5-year survival rate of 16%, despite of all advanced targeted treatment modalities. Like any other cancer, cadherin proteins play a critical role in lung cancer progression, metastasis and drug resistance. Classical type I and type II cadherin proteins are calcium-dependent transmembrane glycoproteins with a cytoplasmic tail that mediates downstream signaling and a large extracellular N-terminal head that engages in homophilic and heterophilic adhesion. While alterations of type I cadherins (N-cadherin and E-cadherin) are well studied, functions as well as alterations of type II cadherins, such as cadherin-8, -9, -10, -12, and -18, remain largely unknown. Recent whole genome sequencing of patient samples towards Precision Medicine initiatives revealed 2,687 donors affected by 9,151 cadherin10 (CDH10) mutations alone across the 63 cancer projects worldwide. The majority of mutations in CDH10 are missense substitutions largely distributed throughout the entire gene length, without any specific hotspot. CDH10 copy number amplification is also reported in a significantly large number of lung cancer patients. Alternative splicing of this gene potentially results in multiple transcript variants. To resolve the conundrum of Loss-of-heterozygosity (LOH) and copy number amplification, we decided to look further in to expression and function of CDH10 using array of lung cancer cell lines and human lung cancer patient samples. Here we report, for the first time, that full-length CDH10 expression as well as the tumor suppressive function are compromised in the course of NSCLC development, while aberrant smaller isoforms appear in the cell lines and tumors that drive the oncogenic progression. Expression of such smaller isoforms were further altered when the cells were treated with commonly used chemotherapy drugs, such as Cisplatin, Doxorubicin and Paclitaxel indicating a direct relationship between drug resistance and appearance of these smaller isoforms. We found that the downregulation of full-length CDH10 using siRNA results in an increase in proliferation and invasion, indicating a potential anti-oncogenic function of full-length CDH10 protein. Therefore, we found that mutations and alternative splicing potentially downregulates full-length CDH10 expression along with its tumor suppressive function. However, appearance of smaller aberrant isoforms accounts for tumorigenic progression and drug resistance. Citation Format: Rajib Ghosh, Phattrakorn Powan, Liying W. Rojanasakul, Yon Rojanasakul. Isoform specific expression of cadherin10 is associated with progression and drug resistance in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5159.