Small cell lung cancer (SCLC) is characterized by aggressive growth, genomic heterogeneity, and rapid development of resistance to chemotherapy. SCLC patients frequently demonstrate initial clinical response to chemotherapy, including the clinical standard of care cisplatin-etoposide regimen, but eventually succumb to chemo-refractory disease. Recent sequencing studies have demonstrated that SCLC is one of the most highly mutated cancers, but these efforts have yet to identify targetable `driver' mutations in both chemo-sensitive and chemo-refractory disease. Using an unbiased, high-throughput cellular screen of a diverse chemical library, we have identified that SCLC chemo-sensitive and chemo-refractory tumor cells are highly sensitive to inhibitors of the general transcription apparatus. In particular, we observed that SCLC tumor cells were highly sensitive to THZ1, a newly identified covalent inhibitor of cyclin-dependent kinase 7 (CDK7) that functions as a co-factor for RNA polymerase II (Pol II). We found that this transcriptional vulnerability is conferred, in part, by the exquisite sensitivity of key super-enhancer (SE) -driven SCLC oncogenes to transcriptional inhibition. We therefore hypothesize that the inhibition of other transcriptional CDKs found at SEs and their associated genes could provide additional therapeutic avenues. For this purpose we have developed structure-inspired approaches for the design of covalent inhibitors targeting various transcriptional CDKs. We further hypothesize that comparative analysis of enhancer landscapes and gene expression profiles from chemo-nave and chemo- refractory primary tumors will 1) identify transcriptional and epigenetic features specific to chemo-refractory disease, 2) enable grouping into clinically relevant subtypes, and 3) identify transcriptional and epigenetic dependencies specific to chemo-refractory disease that can be `drugged' using transcriptional CDK inhibitors. As changes to tumor oncogene expression and chemo-resistance have been shown to impact the immune compartment, we anticipate that chemo-refractory tumors will also exhibit changes in immune cell activation and infiltration. By extending our classification of clinical subtypes to the tumor microenvironment, we hope to find both tumor and immune cell gene expression programs that amenable to small molecule targeting with the goal of enhancing tumor immune surveillance capabilities. Lastly, as many transcription CDKs are known to transcriptionally regulate key pathways that modulate the response to DNA-damaging agents and immunotherapies we will investigate whether transcriptional CDK inhibitors may also be combined with other investigational SCLC therapies.
Small Cell Lung Cancer (SCLC) rapidly develops resistance to first-line chemotherapy. There are currently no treatment options for patients with chemo-refractory disease leading to a very poor prognosis. Building on promising initial results in preclinical SCLC models, this proposal aims to investigate the therapeutic potential of CDK inhibitors for broadly targeting transcriptional and epigenetic dependencies in chemo-refractory SCLC.
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