Identification of synthetic lethal genetic interactions of SWI/SNF complex subunits
Hypothesizing the existence of functional genomic interactions that affect cellular viability, we have performed a genome-wide CRISPR-Cas9 knockout screen on pairs of SMARCA4 mutant and WT isogenic lung cancer cell lines (Fig. 1). The hits, putative synthetic lethal partners of SMARCA4, will be validated by orthogonal approaches in vitro and in vivo. Prioritization will be given based on the therapeutic accessibility of targets to aid in faster translation of discoveries. One such hit is SMARCA2 which we intend to validate further.
Importantly, we have developed potent chemical probes to degrade SMARCA2, a synthetic lethal partner of SMARCA4 and top hit from our screens. If successful, these studies will provide novel lung cancer therapeutic targets.
Fig. 1 Genome-wide CRISPR knockout screen is a powerful approach to discover synthetic lethal partners in isogenic SMARCA4 mutant and WT cell lines.
Discover and develop proteolysis targeting chimeras (PROTACs) as cancer therapeutics
An important aspect of our research interest is the development of chemical probes to supplement genetic tools to understand chromatin biology in cancer. Proteolysis targeting chimeras (PROTACs) are exciting new molecular entities that have unique and potent pharmacologic properties. We have developed several PROTACs that induce selective degradation of target oncoproteins of interest including SMARCA2 as a therapeutic for SMARCA4 mutant lung cancer and glucocorticoid receptor (GR) as a combination therapy to circumvent resistance to chemotherapy in lung cancer (Fig. 2). These studies will provide first-in-class lung cancer therapeutics for clinical development.
Fig. 2 Chemical structures of some GR and SMARCA2 PROTACs synthesized in collaboration with talented and dedicated medicinal chemists (e.g. J.T Link on GR PROTACs).
Approaches and Innovations
Novel lung adenocarcinoma models
We have established several novel lung cancer mouse models termed KPS and KPA driven by loss of SMARCA4 and ARID1A respectively in various combinations with p53 loss and Kras mutations (KrasLSLG12D/WT, p53fl/fl, Smarca4fl/fl or Arid1afl/fl). Additionally, we have genomically profiled novel patient-derived xenograft (PDX) tumors accessed from the MD Anderson Lung Cancer Moonshots.
Novel synthetic lethal genetic interacting partners of SMARCA4
Genome scale CRISPR knockout screen has identified novel targetable synthetic lethal partners to SMARCA4.
First-in-class SMARCA2 PROTACs
A major innovation of our laboratory is the discovery of the potent SMARCA2 degrading PROTACs. These molecules will be extremely useful in deciphering the utility of targeting SMARCA2 as a synthetic lethal therapy in SMARCA4 mutant tumors as well as dissecting the changes in chromatin landscape and transcriptional responses to perturbation of the SWI/SNF complex.
First-in-class GR PROTACs
Another prominent innovation of our lab is the use of first-in-class potent and specific GR degrading molecules that are active in vivo to investigate the role of GR in cancer. These molecules are excellent research tools and have the potential to be further developed into highly relevant therapeutics to combat chemotherapy resistance in other solid tumors including lung cancer.
In summary, the investigation of novel molecules based on a new technology in existing and novel disease model systems will be a paradigm shift in the study of chromatin biology in lung cancer.