Potential New Therapeutic Target Identified in TNBC

Leslie Parise, PhD, a UNC Lineberger member and professor and chair in the UNC School of Medicine Department of Biochemistry and Biophysics

Leslie Parise, PhD

CIB1, which is associated with cancer cell survival and proliferation, could represent a novel target for the development of targeted therapies in triple-negative breast cancer (TNBC), according to an analysis published in the journalBreast Cancer Research and Treatment.

CIB1 is a 22-kDa regulatory protein that is commonly hijacked by cancerous cells to avoid normal apoptosis. Prior studies have shown that CIB1 depletion disrupts the PI3K/AKT and RAS/MEK/ERK pathways, resulting in a synergistic mechanism of cell death.

“We think that cancer cells become addicted to CIB1 for their survival, so when we remove CIB1 from susceptible cancer cells, they can no longer survive,” Leslie Parise, PhD, a UNC Lineberger member and professor and chair in the UNC School of Medicine Department of Biochemistry and Biophysics, said in a statement. “We think there is a synergy that occurs from the loss of these two cancer-causing pathways, and when both of them are turned off at once, we observe a catastrophic death of cancer cells."

For the analysis, researchers at the UNC Lineberger Comprehensive Cancer Center explored inducible RNAi depletion of CIB1in vitroandin vivoon 11 TNBC cell lines. All cell lines were examined using immunoblotting clonogenic assay, flow cytometry, RNA-sequencing, bioinformatics analysis, and Kaplan—Meier survival analysis.

TNBC cell lines were transduced with a control or two separate CIB1 shRNA targeting sequences. Overall, CIB1 depletion demonstrated significant signs of cell death. Across all cell lines, the response rate was 72.7%. There was a trend toward better responses in tumor cell lines with higher differentiation scores, although this was not statistically significant (P= .0695).

The most dramatic responses were seen in MDA-MB-468 cell linesin vivo. The MDA-468 cell line demonstrated a near 50% relative change compared with the control arm. This was seen with both CIB1 shRNA depletion methods. Additionally, significant changes were seen in the BT549 cell line, at a near 65% relative change.

A deep analysis of cell lines revealed potential biomarkers of response to CIB1 inhibition, including elevated AKT activation and low PTEN expression. Additionally, RNA sequencing showed decreased proliferation and increased cell death with CIB1 depletion.

“These results highlight the exciting potential of CIB1 as a novel therapeutic target for triple-negative breast cancer,” Parise said. “There is an obvious and pressing need for targeted therapies for triple negative breast cancer patients, who are faced with limited treatment options.”

The authors of the study theorized that depletion of CIB1 would be less toxic to normal cells because they are not addicted to the CIB1 pathway as a means of survival. This could translate to lower adverse events, if a targeted therapy against CIB1 were developed. However, this observation would need to be validated in clinical trials.

“We believe that this protein could be a potentially safe therapeutic target for triple-negative breast cancer, and the future could bring drugs that specifically target this protein to kill breast cancer cells,” Parise added.

The TNBC cell line studies lay the foundation for future research. Based on the promise of the results, the researchers involved in the investigation have founded a new company labeled Reveris Therapeutics to help bring a CIB1 therapy to market. The company is being founded in partnership with the University of North Carolina at Chapel Hill’s Carolina Kickstart program, which is meant to support UNC faculty to commercialize biomedical discoveries.

Black JL, Harrell JC, Leisner TM, et al. CIB1 depletion impairs cell survival and tumor growth in triple-negative breast cancer. Breast Cancer Research and Treatment [published online ahead of print 24 June 2015].