Scientists at Dana-Farber Cancer Institute and University of Texas Southwestern Medical Center Discovery suggests a new strategy for attacking high-profile but elusive target in cancer

Dana-Farber Cancer Institute and University of Texas Southwestern Medical Center scientists have presented drug developers with an unprecedented targeting of a highly dangerous molecular cause of cancer.

The study targets a mutant form of the protein KRAS. This specific protein has proven to be untouchable by current therapies despite it being commonly altered in human cancers. The researchers identified the KRAS’s basic structure as a “dimer.” Its ability to function depends on the composite of two similar or identical proteins. That being said, KRAS can’t work if it is not a dimer. This finding has raised the possibility that drugs that inhibit the mutant KRAS from forming a dimer could in turn impede the protein’s ability to drive cancer growth.

Pasi A. Jänne, MD, PhD, senior author of the new study stated, “The KRAS gene is one of the most frequently mutated genes in human cancers. It’s mutated in 20-25 percent of lung cancers, making it the largest genomic subtype of lung cancer, as well as in a large percentage of colon, pancreatic, and other cancers. That kind of prevalence has made the KRAS protein one of the prime targets for new therapies. So far, however, it has resisted targeting with small-molecule drugs.”

While drugs capable of blocking the process of forming protein dimers do not currently exist for cancer or any other disease, this discovery reported by Jänne and his colleagues could potentially ignite new research in this area, the study authors state.

The Lead Author of the study Chiara Ambrogio, PhD said, “Our findings suggest that dimerization appears to be an essential aspect of KRAS’s role within the cell.” Pasi A. Jänne added, “On the one hand, in the dimer formed by normal and mutant KRAS, the normal portion counteracts the negative effect of the mutant portion. At the same time, we’ve shown that dimerization is critical for KRAS mutants to be fully oncogenic, or cancer-causing. This reliance on dimerization suggests that disrupting dimerization with novel therapies may be an effective way of attacking some cancers at their root.”

The KRAS gene exists in two copies, and each is inherited from the parent. When one copy of KRAS is mutated, potentially speeding up cell growth, the normal copy then reins it back in. In the new study, researchers sought to understand how the normal copy achieves this restraining effect.

To learn more about this study, visit the Dana-Farber website.

The other co-lead authors of the study are Jens Köhler, MD, of Dana-Farber and Zhi-Wei Zhou, PhD, of University of Texas Southwestern Medical Center. David Santamaria, PhD, of the University of Bordeaux, France, is a co-senior author. Co-authors are Raymond Paranal, Jiaqi Li, Marzia Capelletti, PhD, Cristina Caffarra, PhD, and Shuai Li, MD, of Dana-Farber; Haiyun Wang, PhD, and Qi Lv, of Tongji University, China; Sudershan Gondi, PhD, John C. Hunter, and Jia Lu, PhD, of University of Texas Southwestern Medical Center; and Roberto Chiarle, MD, of Boston Children’s Hospital and the University of Torino, Italy.

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