Abstract A143: Identification of the synergistic drugs in combination with EGFR therapy that can target ASCL1+ Lung Adenocarcinoma (A+ LUAD)
Authors: Gupta Kshama , Kosari Farhad 
Published: March 2020

Introduction: Lung cancer is the leading cause of cancer death in the U.S. and in the world. In 2018, lung cancer alone resulted in 25.3% of all cancer deaths evaluated worldwide. Lung Adenocarcinoma (LUAD) is a major subtype of lung cancer and accounts for 40% of these tumors. Our group has recently discovered that about 20% of LUAD are characterized by abnormally high expression of the neuroendocrine transcription factor, ASCL1. In these tumors, ASCL1 orchestrates a network of genomic changes that create opportunities for treatment. We have shown that LUAD tumors expressing high ASCL1 have RET mRNA levels that are predictive of patient survival (p &lt; 0.004), and, these tumors were susceptible to EGFR inhibitors, with having a functional interaction between RET and EGFR. We found EGFR inhibitor, Lapatinib, to have highest efficacy, indicating it to be a primary drug treatment for ASCL1+ (A+) LUAD. However, we and others have observed Lapatinib induces resistance to EGFR therapy over time, and, Lapatinib therapy associated by-pass signaling pathways have recently gained attention. Therefore, we hypothesize that for a long lasting therapy, it is important to identify additional drugs that in combination with EGFR inhibitor Lapatinib will eliminate A+ LUAD tumors. Methodology and Results: An in vitro preliminary screen of approx. 2000 FDA approved small molecule inhibitors done with A+ and A- LUAD cell lines in collaboration at NIH revealed potential candidates for alternative pathways, 80 of which showed a differential sensitivity to A+ LUAD as single agent. We identified best 28 drugs in total: 23 selected from this pre-screen (based on their effectiveness to A+LUAD lines) and 5 additional chosen based on their biological relevance to the disease, which may act upon putative compensatory pathways in EGFR therapy resistance. Our in vitro drug screening in HCC1833 ASCL1+ and ASCL1 knockdown lines has revealed 8 out of 28 drugs to synergize as per their IC50 and fixed ratios, with Lapatinib. From these 8 leads, we have confirmed a definite synergy of Lapatinib with DDR-1 7rh, an inhibitor of ECM receptor DDR-1, using Mac-Synergy-II software. DDR-1, Discoidin domain receptor-1, is a collagen receptor highly upregulated in NSCLC, and is associated with poor prognosis in LUAD. Our microarray data on lapatinib treated tumors from mice PDX has shown ECM signatures to be among top upregulated. Additionally, TM4SF1, a signaling molecule associated with DDR-1, was found to associate with poor outcome in A+LUAD (P=0.0001). Other synergistic drugs identified include, a K+ channel opener (Retigabine), Wnt signaling and Lyn kinase inhibitors (PRI-724, and Bafetinib), Tubulin inhibitor (Docetaxel) and 3 multi-tyrosine kinase inhibitors. Interestingly, Wnt pathway was found to be elevated in Lapatinib treated ASCL1+LUAD in our microarray data. Moreover, Wnt signaling in known to crosstalk with ECM and DDR-1 in other tumors. K+ channel dysfunction is associated with neuronal/neuroendocrine disorders and Lyn kinases are the predominant SRC kinases in brain tumors, indicating their possible involvement in ASCL1+ neuroendocrine tumor pathophysiology. Conclusion: Taken together this data reveals a potential involvement of ECM (DDR-1 receptor) and Wnt signaling in effect of Lapatinib, and the identified leads as path to novel combination therapies for A+ LUAD.

Citation Format: Kshama Gupta, Farhad Kosari. Identification of the synergistic drugs in combination with EGFR therapy that can target ASCL1+ Lung Adenocarcinoma (A+ LUAD) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A143. doi:10.1158/1535-7163.TARG-19-A143