Study demonstrates novel approach to target activator-dependent cancers

As researchers have identified several genes responsible for prostate cancer, a new study published in Nature reveals the puppeteer controlling the strings.

The chains: carcinogenic or oncogenic genes, such as the androgen receptor, FOXA1, ERG and MYC.

The Puppet Master: A chromatin remodeling complex called SWI / SNF, which controls how DNA is arranged and compacted to fit into a cell’s nucleus. A key subunit of this complex provides energy to unwrap DNA to provide access to enhancer elements that stimulate the expression of carcinogenic genes.

In the present study, researchers at the University of Michigan Health Rogel Cancer Center demonstrated that the SWI / SNF complex facilitates access to activators to which oncogenes can bind and drive downstream gene expression in cancer. Degrading a subunit of this complex blocks oncogenes, like cutting the strings of the puppeteer.

This discovery reveals a new approach to the treatment of prostate cancer fueled by different genetic factors, which together account for more than 90% of all prostate cancers.

In human cells, DNA is wrapped tightly around histone proteins, collectively called chromatin. These form a physical barrier to all DNA-based processes. Specialized protein machines have evolved that consume energy and modulate the physical state of DNA for its functional activation. These complexes work in close collaboration with DNA binding regulatory factors called transcription factors to confer distinct cellular identity and function.

“This is the first demonstration in the field of cancer that blocking access to chromatin can be continued as a route to treat cancer. By compacting the chromatin around these enhancer elements, transcription factors are prevented from binding to enhancer elements that lead to cancer, ”said the study author. Arul M. Chinnaiyan, MD, Ph.D., director of the Michigan Center for Translational Pathology and SP Hicks, professor of pathology and urology at Michigan Medicine.

Researchers looked at several models of prostate cancer that expressed different oncogenes. They found that blocking the SWI / SNF complex slows the growth of cancer cells and induces cell death, especially in tumors induced by FOXA1 or the androgen receptor. There was no effect on benign prostate cells.

In normal development, the SWI / SNF complex is essential. “Normal cells can survive with default levels of gene transcription, but cancer cells are particularly dependent on these enhancer regions. They need access to these activators to increase the expression of oncogenic targets, ”Chinnaiyan said.

Components of the SWI / SNF complex are mutated in a number of cancers, but rarely in prostate cancer. Prostate cancers induced by the androgen receptor or FOXA1 were more sensitive to a SWI / SNF degrader than even cancers in which the subunits were mutated.

“Without having mutations, and with only oncogenic transcription factors involved, prostate cancer cells were extremely sensitive to this degradant, even more so than lung cancer where a component of the pathway was mutated,” Chinnaiyan said. . “By disabling this SWI / SNF complex, we found preferential activity against certain cancers and no toxicity in normal cells or normal tissues. This bodes well for clinical studies using compounds that target this pathway. “

He also suggests the possibility of using this approach for other types of cancer that are dependent on oncogenic transcription factors, including certain multiple myelomas and other blood cancers.

The researchers used a SWI / SNF degrader under development by the Indian company Aurigene Discovery Technologies. These compounds are under development for future clinical trials.

The Rogel team will continue to study the biology of this complex, help develop compounds that target this complex, and assess what other types of cancer might respond to this approach. For prostate cancer, they are exploring in the laboratory a combination therapy using the SWI / SNF degrader with anti-androgen therapy. This approach is not yet in clinical trials.

Additional authors: Lanbo Xiao, Abhijit Parolia, Yuanyuan Qiao, Pushpinder Bawa, Sanjana Eyunni, Rahul Mannan, Sandra E. Carson, Yu Chang, Xiaoju Wang, Yuping Zhang, Josh N. Vo, Steven Kregel, Stephanie A. Simko, Andrew D Delekta, Mustapha Jaber, Heng Zheng, Ingrid J. Apel, Lisa McMurry, Fengyun Su, Rui Wang, Sylvia Zelenka-Wang, Sanjita Sasmal, Leena Khare, Subhendu Mukherjee, Chandrasekhar Abbineni, Kiran Aithal, Mital S. Bhakta, Jay Ghurye, Xuhong Cao, Nora M. Navone, Alexey I. Nesvizhskii, Rohit Mehra, Ulka Vaishampayan, Marco Blanchette, Yuzhuo Wang, Susanta Samajdar, Murali Ramachandra

Funding: Prostate Cancer Foundation Challenge Award, National Cancer Institute Grants P50-CA186786, R35-CA231996, U01-CA214170, P30-CA046592, Department of Defense Prostate Cancer Research Program W81XWH-21-1-0500 . Chinnaiyan is a Howard Hughes Medical Institute Fellow, A. Alfred Taubman Fellow, and Professor at the American Cancer Society.

Disclosure: S. Sasmal., LK, SM, CA, S. Samajdar, KA and MR are affiliated with Aurigene Discovery Technologies. JG, MSB and MB are affiliated with Dovetail Genomics. AMC is a co-founder and sits on the scientific advisory boards of LynxDx, Oncopia and Esanik. AMC sits on the Scientific Advisory Board of Tempus and Ascentage.

Cited article: “Targeting SWI / SNF ATPases in activator-dependent prostate cancer”, Nature. DOI: 10.1038 / s41586-021-04246-z

Comments are closed.