Dual targeting of cGAS-STING and splicing to prime lung cancer immunogenicity

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Project Summary Lung cancer is the leading cause of cancer-related death in the United States. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and despite aggressive treatment strategies that include medical therapy, surgical resection, and radiation therapy, 5-year survival rates for patients with lung cancer remain dismal. Recently, the US Food and Drug Administration (FDA) approved several immune checkpoint inhibitor-based therapies for the treatment of NSCLC, establishing immunotherapy as an effective therapeutic option and standard-of-care treatment for NSCLC. Despite this, many patients fail to respond to immune checkpoint blockade (ICB) and the subgroup of patients with KRAS and STK11 commutations (KL) has emerged as a particularly aggressive, immunosuppressive form of NSCLC resistant to ICB. Our group has recently discovered that by treating KL-mutated NSCLC with epigenetic de-repressing agents, expression of a key protein in the immune response against lung cancer, stimulator of interferon genes (STING), is restored. When stimulus for the STING pathway is subsequently provided through pulsed inhibition of a spindle assembly checkpoint protein, monopolar spindle 1 (MPS1), potent anti-tumor responses occur, restoring sensitivity to ICB. While these findings have yet to be validated in clinical samples of KL-mutated NSCLC, these samples are now available to use for study. Validation of this therapeutic strategy will show that it is possible to overcome KL-mutation induced immunosuppression, though, it does not generate neoantigens to drive durable anti-neoplastic immune responses. Fortunately, MPS1 shares kinase homology with CDC2-like kinase (CLK2), a key regulator of mRNA splicing, and dual MPS1/CLK2 inhibitors have been developed. This provides the unique opportunity to additionally dive durable anti-tumor immune responses through simultaneous pharmacological disruption of mRNA splicing. Indeed, pharmacological modulation of splicing was recently demonstrated as a definitive, untapped method to generate neoantigens that elicit anti-tumor immune responses. The overall goal of this fellowship proposal is, therefore, to provide advanced post-doctoral training in translational cancer immunotherapy research while evaluating a novel approach to enhance immunogenicity in a highly aggressive and resistant form of NSCLC. We will accomplish this by (1) validating the effect of epigenetic de-repression of STING and pulsed MPS1 inhibition in clinical samples of ICB-resistant, KL-mutated NSCLC and (2) examining mRNA splice disruption and neoantigen generation in dual MPS1/CLK2 inhibitor treated KL-mutated NSCLC. Together these aims will seek to improve therapeutic outcomes for patients with NSCLC while enhancing the pool of highly trained physician-scientists.