Grant: Project Grant

Cancer is a heterogeneous disease.  Distinct subtypes of cancers from the same primary site of origin can be defined by their unique molecular pathological features. Consequently, cancer therapy is shifting towards strategies aimed at genes specific to each patient, where mutated cancer-causing genes in tumors are targeted by highly selective inhibitors. These drugs are often very effective and have minimal side effects as normal tissues do not harbor the cancer-causing mutations, which are being targeted. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and is the leading cause of cancer death worldwide and in Canada. NSCLC consists of different subtypes characterized by distinct cancer-causing mutations. For subtypes with mutations activating genes such as EGFR (10-35%) or ALK (3-7%), there are potent drugs that target these activated gene products and have significantly improved patient survival. In contrast, 10-37 % of NSCLCs are deficient in SMARCA4, a known tumor suppressor gene lost in many cancer types and which to this date remains undruggable. Therefore, effective treatment of these patients remains an unmet clinical challenge. In this proposal, we will first exploit a molecular weakness of SMARCA4-deficiceny in NSCLCs. We have previously uncovered a vulnerability of SMARCA4 loss in an ovarian cancer subtype, which can be targeted using an FDA-approved drug originally developed for treating breast cancers. To extend our findings to NSCLCs, we will use a variety of model systems, including cell culture, mouse preclinical cancer models, and tumor samples from lung cancer patients. Independently, we will use powerful genetic tools to identify novel vulnerabilities of SMARCA4-deficiceny in NSCLCs that can be exploited therapeutically. Our goal is to provide potential treatment strategies to treat SMARCA4-deficient NSCLCs and provide a clinical benefit for cancer patients.