RAS inhibitors for use in fighting more cancers

Date:
November 4, 2021
Source:
UT Southwestern Medical Center
Summary:
New findings help better understand the how one of the most
commonly mutated genetic drivers of cancer passes signals that
cause the disease.



FULL STORY ==========================================================================
New findings by UT Southwestern researchers help better understand the
how one of the most commonly mutated genetic drivers of cancer passes
signals that cause the disease.


==========================================================================
The study, published in Nature Structural & Molecular Biology, focuses
on a family of proteins called RAS, which is mutated in 20 to 25% of
all cancers, especially in lethal cancers such as pancreatic, colorectal
and lung cancers.

"A framework to develop RAS inhibitor strategies is badly needed because recently approved RAS inhibitors such as sotorasib only work against one specific mutation, and many other RAS mutations also cause cancer," said Kenneth Westover, M.D., Ph.D., Associate Professor of Radiation Oncology
and Biochemistry, member of the Chemistry and Cancer Research Program
in the UT Southwestern Harold C. Simmons Comprehensive Cancer Center,
and an author of the study. "This work sets the stage for development of
new targeted RAS inhibitors to address major drivers of lethal cancers,
such as pancreatic and colon cancer." Starting in 2012, Dr. Westover's
lab worked with the Dana-Farber Cancer Institute to develop drugs that
bind to a specific RAS mutant where a glycine amino acid at position 12
in the RAS protein is changed to a cysteine, the so- called KRAS G12C.

"Cysteine is a distinctive amino acid that allows us to irreversibly
attach drugs using special chemistries. Other major cancer-associated
RAS mutations do not give us the same foothold," Dr. Westover said.

His lab's work helped propel the field that saw approval of one KRAS G12C inhibitor, sotorasib, in May. Approval of an analogous drug, adagrasib,
is widely anticipated.

In the latest study, the Westover lab sought to understand how
cancer-causing RAS mutants pass inappropriate signals from the surface
of the cell to the cell nucleus. The formation of large protein clusters
as part of the mechanism was known, but the clusters' structure was
unknown. Dr. Westover and collaborators used computer simulations to
arrive at an atomistic structural model of a RAS assembly and validated
the model using biological systems.

"This structural model is now available to the wider RAS research
community. We hope it will enable researchers to test new ideas about
how RAS works in normal physiology and new strategies for targeting cancer-causing RAS mutations," said Carlos L. Arteaga, M.D., Director
of the Simmons Cancer Center.

Because RAS signaling relies on formation of RAS complexes, Dr. Westover
thinks it may be possible to create new generations of RAS-targeted
drugs that work by breaking apart such RAS complexes.

Funding for the study came from the National Cancer Institute, the
Department of Defense, and the Cancer Prevention and Research Institute
of Texas.

========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Venkatesh P. Mysore, Zhi-Wei Zhou, Chiara Ambrogio, Lianbo Li,
Jonas N.

Kapp, Chunya Lu, Qi Wang, Maxwell R. Tucker, Jeffrey J. Okoro,
Gabriela Nagy-Davidescu, Xiaochen Bai, Andreas Plu"ckthun,
Pasi A. Ja"nne, Kenneth D. Westover, Yibing Shan, David
E. Shaw. A structural model of a Ras-Raf signalosome. Nature
Structural & Molecular Biology, 2021; 28 (10): 847 DOI:
10.1038/s41594-021-00667-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211104162559.htm

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