Identifying the Genomic Landscape of CDK4/6i Resistance in Patients with HR+/HER2- Metastatic Breast Cancer

Investigators have established a genomic outline of the CDK4/6i resistance in patients with breast cancer, growing the potential for novel treatments to circumvent that resistance.

Researchers have established that the genomic landscape of resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is heterogeneous with multiple potential mediators.

After performing whole exome sequencing (WES) on metatatic tumor biopsies from 58 patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer who received a CDK4/6i with or without an antiestrogen, the researchers characterized 69.5% as resistant (either intrinsic or acquired) and 30.5% as sensitive. In order to validate putative resistance mediators found in patient samples, HR-positive/HER2-negative cells were modified via CRISPR knockout or lentiviral overexpression.

In parallel, HR-positive/HER2-negative breast cancer cells were cultured to resistance in the presence of an escalating dose of CDK4/6i. Derivative cell lines were subjected to western blotting in an effort to interrogate the putative resistance mediators. Novel dependencies were found in these derivative cell lines by using treatment with targeted therapeutic agents in vitro.

Following these methods, the WES of tumors with CDK4/6i exposure revealed candidate mechanisms of resistance including biallelic RB1 disruption (n=4, 10%). They also revealed activating events in AKT1 (n=5, 12.5%), RAS (n=4, 10%), aurora kinase A (AURKA, n=11, 27.5%), and cyclin E2 (CCNE2, n=6, 15%).

Knockout of RB1 and overexpression of the activating events caused CDK4/6i demonstrated concordant acquisition of RB1 downregulation, RAS/ERK activation, AURKA overexpression, and CCNE2 overexpression.

Based on these results, the researchers were able to state that the genomic landscape of resistance to CDK4/6i is heterogeneous with multiple potential mediators that play well-established roles in cell division and oncogenic signal transduction. They found novel mechanisms of clinical resistance, including activation of AKT1 and RAS family oncogenes, as well as amplification of AUKRA and CCNE2. In vitro, these drivers provoked CDK4/6i resistance. Finally, in each case, a novel dependency was identified, which was translatable into the clinic setting.

The researchers argued that the results demonstrate the future potential of next-generation sequencing as a tool to enable identification of resistance mediators. Similarly, they said that the presence of specific genomic alterations may define new therapeutic opportunities in CDK4/6i resistance.

REFERENCE

Wander SA, Cohen O, Gong X, Johnson GN, et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in patients with hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC). Accessed Dec 4, 2019. https://plan.core-apps.com/sabcs2019/abstract/c3d31d6ffb8feb46fe802df1c905011e