Abstract
Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA4/2 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-Jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.
Highlights
Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable
We first examined the potential correlation between SMARCA4 status and cyclin D1 expression in nonsmall cell lung cancer (NSCLC) cells as seen in SCCOHT
Despite the differences in tissue origins and mutation burdens between these two cancer types, SMARCA4-deficient NSCLC cell lines (n = 11) express lower levels of cyclin D1 protein (Fig. 1a) and messenger RNA compared to SMARCA4proficient NSCLC cell lines (n = 9), which consist of the major NSCLC subtypes with KRAS (n = 4) or EGFR (n = 3) mutations as well as those without these driver mutations (n = 2; Supplementary Data 1)
Summary
Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. Previous studies have uncovered several synthetic lethal interactions of SMARCA4 loss in NSCLC cells, including suppression of SMARCA28,9, a non-catalytic activity of EZH210, and aurora kinase A11. These vulnerabilities associated with SMARCA4 deficiency are currently not druggable with any FDAapproved agents. In the case of SCCOHT, the critically low level of cyclin D1 caused by SMARCA4 loss is a cancer vulnerability that can be targeted by the same inhibitors We investigated this synthetic lethal interaction in SMARCA4-deficient NSCLC, which has a complex mutation landscape, and explored the potential strategy of using CDK4/6 inhibitors to treat this highly aggressive subgroup of lung cancer
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