Functional Genomics to Guide Cancer Therapy
Our laboratory uses functional genomic tools to study cancer-relevant pathways and to guide cancer therapy. We aim to identify novel genes and networks that modulate response to cancer drugs and to uncover genetic dependencies in cancer that can be exploited therapeutically.
Overcoming drug resistance to targeted cancer therapeutics
Drug resistance remains a major clinical challenge for cancer therapy. Not all patients respond to the same treatments and many patients who initially respond to the therapies develop drug resistance. This is true not only for the conventional chemotherapies and genotype-directed drugs targeting cellular components altered in cancers but also for the immunotherapies which harness the immune system to target tumor cells. Thus, a better understanding of resistance mechanisms is essential to enable the rational development of treatment options to overcome this clinical challenge.
Unbiased functional genetic screens have been proven to be powerful in uncovering novel genes and network interactions that modulate response to cancer therapeutics (PMID: 24657533). Using this systematic approach, we have previously discovered novel resistance mechanisms to inhibitors targeting receptor tyrosine kinases (RTKs) and the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC), melanoma and colorectal cancer (see Publications). The mechanistic insight of these studies also allowed us to identify potential treatment strategies to overcome drug resistance, one of which has been validated in clinical trials (NCT01719380, NCT02164916, NCT02928224) and recently approved by the FDA.
Currently, we are investigating drug resistance mechanisms to inhibitors targeting ALK/ROS1 RTKs and cyclin-dependent kinases (CDK) 4/6, which have been approved by FDA to treat subtypes of NSCLC and breast cancer, respectively (PMID: 27598681; 27030077). We are also studying tumor-intrinsic function and regulation of PD-L1, an inhibitory immune checkpoint protein often upregulated in cancer cells to escape immune surveillance (PMID: 26598942). Our goal is to identify effective treatment strategies to overcome drug resistance and enhance the clinical utilities of these cancer therapeutics.
Targeting genetic dependencies of cancer driver mutations
Genotype-directed anticancer drugs often target gain-of-function oncogenic mutations in cancer cells and thus have fewer side effects in normal tissue. However, some cancer driver mutations such as loss-of-function alterations in tumor suppressors are not directly actionable. In this context, “synthetic lethality” is often employed to identify alternative drug targets whose inhibition is selectively lethal to the cancer cells harboring these hard-to-treat mutations.
Inactivation of SWI/SNF chromatin remodeling genes is known to cause cancers (PMID: 21654818; 26601204). Deleterious mutations in SMARCA4, a key SWI/SNF component, underlie the rare but often lethal cancer of young women – small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) (PMID: 24658001; 24658002; 24658004). Similarly, rare but highly aggressive atypical teratoid/rhabdoid tumors (AT/RTs) affecting the central nervous system in children are attributable to inactivating mutations in another SWI/SNF member, SMARCB1 (PMID: 9671307; 9892189). In addition, SMARCA4 is also frequently inactivated by mutations and other mechanisms in common cancers such as NSCLC (PMID: 12566296; 21280140; 25079552). However, the underlying mechanisms of SWI/SNF loss in driving tumorigenesis are currently unclear. Thus, SWI/SNF-deficient cancers still lack rationalized and targeted treatment options.
We have previously linked several chromatin factors altered in cancers to oncogenic pathways and identified potential treatment strategies (see selected publications). Recently, we uncovered a common druggable vulnerability shared by SMARCA4-deficient SCCOHT and NSCLC: SMARCA4-loss in these cancers causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition (PMID: 30718506, 30718512). These results suggest that FDA-approved CDK4/6 inhibitors could be effective to treat these aggressive cancers. This is currently being tested as a part of the Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR) (NCT03297606) based on our findings.
Currently, we are using druggable gene-family shRNA/CRISPR libraries and compound collections to identify other SWI/SNF synthetic lethal targets in SCCOHT, AT/RT, and NSCLC. Furthermore, we aim to reveal the driver pathways of SWI/SNF loss using complementary functional genetics and biochemical tools. Our goal is to uncover and target vulnerabilities of these hard-to-treat cancers, resulting in clinical benefit for patients.