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Review Articles

RAS and RHO family GTPase mutations in cancer: twin sons of different mothers?

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Pages 386-407 | Received 27 May 2020, Accepted 12 Aug 2020, Published online: 25 Aug 2020
 

Abstract

The RAS and RHO family comprise two major branches of the RAS superfamily of small GTPases. These proteins function as regulated molecular switches and control cytoplasmic signaling networks that regulate a diversity of cellular processes, including cell proliferation and cell migration. In the early 1980s, mutationally activated RAS genes encoding KRAS, HRAS and NRAS were discovered in human cancer and now comprise the most frequently mutated oncogene family in cancer. Only recently, exome sequencing studies identified cancer-associated alterations in two RHO family GTPases, RAC1 and RHOA. RAS and RHO proteins share significant identity in their amino acid sequences, protein structure and biochemistry. Cancer-associated RAS mutant proteins harbor missense mutations that are found primarily at one of three mutational hotspots (G12, G13 and Q61) and have been identified as gain-of-function oncogenic alterations. Although these residues are conserved in RHO family proteins, the gain-of-function mutations found in RAC1 are found primarily at a distinct hotspot. Unexpectedly, the cancer-associated mutations found with RHOA are located at different hotspots than those found with RAS. Furthermore, since the RHOA mutations suggested a loss-of-function phenotype, it has been unclear whether RHOA functions as an oncogene or tumor suppressor in cancer development. Finally, whereas RAS mutations are found in a broad spectrum of cancer types, RHOA and RAC1 mutations occur in a highly restricted range of cancer types. In this review, we focus on RHOA missense mutations found in cancer and their role in driving tumorigenesis, with comparisons to cancer-associated mutations in RAC1 and RAS GTPases.

Disclosure statement

C.J. Der is a consultant/advisory board member for Mirati Therapeutics and Deciphera Pharmaceuticals. C.J. Der has received research funding support from Mirati Therapeutics and Deciphera Pharmaceuticals. C.J. Der has consulted for Ribometrix, Jazz Therapeutics, SVB Leerink, Axon Advisors LLC, Third Bridge, SmartAnalyst, Turning Point Therapeutics and Eli Lilly.

Additional information

Funding

Our research is supported by grants from the National Cancer Institute [R21CA179193, R01CA42978, R01CA175747, R01CA223775, P50CA196510, U01CA199235, P01CA203657 and R35CA232113], Pancreatic Cancer Action Network/AACR [15-90-25-DER], Department of Defense [W81XWH-15-1-0611], and the Lustgarten Foundation [388222].

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