Two new studies found that targeting the cyclin-dependent kinases 4/6 exposed a vulnerability in SMARCA4-deficient cancers.
Cyclin-dependent kinase 4/6 (CDK4/6) inhibition, a treatment used with some breast cancers, might also prove effective against tumor suppressor SMARCA4 (BRG1) mutation-harboring lung cancers and a rare, aggressive form of SMARCA4 mutation-driven ovarian cancer, suggest preclinical findings reported in a pair of papers in Nature Communications.
Loss-of-function mutations inactivate SMARCA4 in approximately 10% of non-small-cell lung cancers (NSCLC) and nearly 100% of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) tumors, noted coauthor William Foulkes, MD, James McGill professor of medicine, oncology and human genetics at McGill University and head of the Cancer Genetics Laboratory, Lady Davis Institute for Medical Research, in Montreal, Quebec, Canada.
“SMARCA4 is a key subunit of SWI/SNF chromatin remodeling complexes regulating gene expression,” explained coauthor Sidong Huang, PhD, assistant professor of biochemistry and member of Goodman Cancer Research Centre at McGill University. “Although epigenetic dysregulation is a known driver of tumorigenesis, it is not clear exactly how loss of SMARCA4 leads to cancer.”
Foulkes previously discovered that loss-of-function mutations in the chromatin remodeling gene SMARCA4 is ubiquitous in SCCOHT in the course of investigating the genetic roots of rare familial ovarian tumors. Working with Huang and others, he also showed that SMARCA4 loss in SCCOHT causes cyclin D1 deficiency, and hence, susceptibility to CDK4/6 inhibitors.
In their newly-reported research, the same was found to be true in NSCLC, the team reported. Huang, PhD student Yibo Xue, and others, identified CDK4/6 as candidate targets for treating SMARCA4 mutation-harboring cancers. They were the “top hits in a screen searching for kinases whose suppression would selectively kill SCCOHT cell lines,” Huang explained.
“In the case of SCCOHT in particular, it is encouraging to find existing drugs that may prove effective because this is such a rare cancer that it is unlikely to be the subject of dedicated drug development,” said Huang.
CDK4/6 inhibitors directly target tumor progression and might also facilitate antitumor immune response. They have been used for years against estrogen receptor (ER)-positive breast cancers, so their safety profile is well understood, noted Foulkes.
The researchers now plan to initiate clinical studies and identify additional molecular targets for combinatorial treatment regimens, Huang said.
“Our goal is to identify other vulnerabilities as well as cancer-causing pathways induced by SMARCA4 loss in SCCOHT and NSCLC that can be exploited therapeutically,” Huang said. “SMARCA4 mutations have been found in other cancers which may have different dependencies than we have uncovered here. This also remains to be studied.”
“We hope to offer CDK4/6 inhibitors to women with SCCOHT and men and women with NSCLC, via our medical oncology colleagues,” Foulkes told Cancer Network. “There are other targets we can identify. Combination therapies are probably needed.”