Project 2: Reversing STING-mediated immunosuppression in LKB1-mutant lung adenocarcinoma

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SUMMARY Project 2 of the Emory Lung Cancer P01 application focuses on the dissection of suppressed anticancer immunity mechanisms involving STING in lung adenocarcinoma (LUAD) with LKB1 mutations for translational gains. Lung cancer is the leading cause of cancer death in the US with limited therapeutic options. While molecularly targeted therapies are effective in patients with defined mutations such as those in EGFR and ALK, immune checkpoint inhibitors (ICI) have brought hope for additional patients and have revolutionized cancer therapy to stimulate the host immune system to destroy tumors. Unfortunately, the majority of lung cancer patients show poor response to such ICIs. In particular, LUAD patients with LKB1 mutations have no targeted therapies and are unresponsive to ICIs. Thus it is urgent to understand the tumor-immune interactions in such LKB1-mutant LUAD and develop new therapeutic approaches to overcome immunotherapy resistance. It appears that the immune suppressed state of LKB1-mutant LUAD is associated with the silenced STimulator of INterferon Gene (STING), a cytosolic DNA sensor that regulates innate immunity. Thus, strategies to reverse STING expression may re-establish the tumor-immune microenvironment and re-sensitize tumors for effective treatment with STING agonists or ICIs. We discovered that birinapant, a small molecule antagonist of Inhibitor of Apoptosis Protein (IAP), can restore STING expression, reactivate STING signaling, and enhance immune effector cell killing of LKB1-mut LUAD cells. In further support of this revised application, our new data showed that birinapant exhibited potent in vivo immune-dependent anti-tumor activity selectively in immune competent LKB1-mutant mouse model. These results led to our central hypothesis that LKB1 loss is associated with STING downregulation through aberrant IAP functions, and pharmacological targeting using IAP inhibitors may restore STING expression and re-establish immune response pathways in LKB1-mut LUAD for enhanced therapeutic efficacy. To test this hypothesis, we propose to use a combination of cell, mouse, and patient tumor tissues from Core 2 and Project 3 clinical trials 1) to examine the molecular mechanisms by which IAP inhibitors induce STING expression in LKB1-mut LUAD cells; 2) to determine the therapeutic effect of IAP inhibitors and STING agonists in LKB1-mut tumors; and 3) to evaluate the therapeutic effect of IAP inhibitors in combination with a PD-1 blockade agent in LKB1-mut tumors. We will examine the impact of the IAP-STING axis in the context of GDH1 (Project 1) and FAK hyperactivation (Project 3) to improve mechanistic understanding of LKB1 immune response signaling. Accomplishing the goals of the proposal, we aim to deliver preclinical evidence for using IAP inhibitors, such as birinapant, alone or in combination with STING agonists or ICI to treat lung cancer patients with LKB1 alterations.