Abstract B26: Novel pro-host role for insulin receptor substrate-1 in lung adenocarcinoma
Authors: Metz Heather E. , Kargl Julia , Busch Stephanie , Kim Kyoung-Hee , Houghton McGarry 
Published: October 2016

Lung cancer is the leading cause of cancer deaths worldwide. In the United States alone, lung cancer accounts for ~160,000 deaths per year while the five-year survival rate remains stagnant at ~15%. Lung adenocarcinoma (ADCA) accounts for over 50% of non-small lung cancer cases. Within this subset, K-ras is the most common activating mutation accounting for ~35% of cases. Kras mutant tumors have remained a largely un-targetable subtype and a better understanding of the signaling pathway involved in the different ADCA subtypes will be necessary for the development of therapeutics. Insulin Receptor Substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many of the pathways that are activated in lung cancer. We have undertaken a controlled study of this protein within the context of lung ADCA. Analysis of a well-annotated human lung ADCA TMA (n=136) revealed that positive IRS-1 staining provided a 75-month median survival advantage among all ADCA cases (p=0.01) and an 81-month median advantage within the K-ras subtype (p=0.006). EGFR and non-K-ras/non-EGFR cases did not display differences. To focus in on the K-ras subtype, we generated LSL-K-ras/IRS-1fl/fl mice and studied them over a time course. LSL-K-ras/IRS-1-/- mice displayed highly significant early mortality (p&lt;0.0001) and increased tumor burden when compared to LSL-K-ras/IRS-1+/+ controls (p&lt;0.01). Interestingly, IRS-1 loss in tumor cells generated a robust immune response. The bronchial alveolar lavage fluid of LSL-K-ras/IRS-1-/- mice showed increased immune infiltration, most prominently neutrophilic (5 times higher). Significant increases in many immune cell-recruiting chemokines were observed in the LSL-K-ras/IRS-1-/- mice compared to controls including CCL2, CCL3, CCL4, CXCL1, CXCL2 and CXCL5. Surprisingly, an array of IRS-1 silenced A549 cells versus controls displayed no change in CC/CXC chemokine production. We decided to investigate which factor could be missing in our in vitro system that is necessary for activation of this chemokine response. IL-17 and IL-22 producing cells, which are present at sites of tumor in human lung cancer cases and LSL-K-ras mice are known to induce CC/CXC chemokine responses. The JAK/STAT pathway is also implicated in this response. We found that loss of IRS-1 increases pSTAT3 production in vivo and in vitro in the presence of IL-22. Finally, we treated LSL-K-ras/IRS-1-/- and LSL-K-ras/IRS-1+/+ controls with a JAK inhibitor (AZD1480). A significant reduction in tumor burden and chemokine response was observed in both genotypes, with the most pronounced response in the LSL-K-ras/IRS-1-/- group. K-ras mutant, IRS-1-low patients represent ~40% of K-ras mutant lung ADCA patients. The phenotype of this group of patients is counter-intuitive in that IRS-1 typically functions in a pro-growth manner. In the setting of certain oncogenic drivers, however, IRS-1 plays an opposing role to this in which its presence actually maintains homeostasis. This work provides evidence that JAK inhibition may be a viable therapeutic option for these patients as well as describes a novel role for IRS-1 as a mediator of immune cell recruitment in lung adenocarcinoma.

Citation Format: Heather E. Metz, Julia Kargl, Stephanie Busch, Kyoung-Hee Kim, McGarry Houghton. Novel pro-host role for insulin receptor substrate-1 in lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B26.