The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS

Li, Chuanchuan; Vides, Alberto; Kim, Dongsung; Xue, Jenny Y.; Zhao, Yulei; Lito, Piro

doi:10.1126/science.abf1730

Cited by 49 publications

(40 citation statements)

References 37 publications

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“…In addition to SOS-catalysed nucleotide exchange, GAP-stimulated GTP hydrolysis was also analysed. While the intrinsic GTP hydrolysis of KRasG13C-edaGTP (t 1/2 = 187 min) is comparable to that of KRasWT:GTP (t 1/2 = 126 min) and even faster than for the KRasG12C mutant (t 1/2 = 300 min) 25 (Figure S15), a drastically decreased GAP-stimulated GTP hydrolysis was observed for the G13C mutant as expected. 26 After a detailed in vitro characterization of the nucleotide analogues, the next experiment was to investigate whether oncogenic signalling could also be inhibited in vivo.…”

Section: Inhibition Of Oncogenic Krasg13c Signalling By Covalent Nucl...supporting

confidence: 72%

“…The copyright holder for this preprint this version posted July 25, 2022. ; https://doi.org/10.1101/2022.07. 25.501348 doi: bioRxiv preprint 3 nucleotide competitive inhibitors that can covalently bind to KRasG12C. 18,19 Strategies involving direct competition with nucleotide binding were originally set aside because of the high affinity of GDP/GTP for Ras and high cellular GDP/GTP concentrations.…”

Section: Introductionmentioning

confidence: 99%

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Targeting oncogenic KRasG13C with nucleotide-based covalent inhibitors

Goebel

Kirschner

Koska

et al. 2022

Preprint

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Mutations within Ras proteins represent major drivers in human cancer. In this study, we report the structure-based design, synthesis, as well as biochemical and cellular evaluation of nucleotide-based covalent inhibitors for KRasG13C, an important oncogenic mutant of Ras that has not been successfully addressed in the past. Mass spectrometry experiments and kinetic studies reveal promising molecular properties of these covalent inhibitors, and X-ray crystallographic analysis has yielded the first reported crystal structures of KRasG13C covalently locked with these GDP analogues. Importantly, KRasG13C covalently modified with these inhibitors can no longer undergo SOS-catalysed nucleotide exchange. As a final proof-of-concept, we show that in contrast to KRasG13C, the covalently locked protein is unable to induce oncogenic signalling in cells, further highlighting the possibility of using nucleotide-based inhibitors with covalent warheads in KRasG13C-driven cancer.

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Section: Inhibition Of Oncogenic Krasg13c Signalling By Covalent Nucl...supporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Targeting oncogenic KRasG13C with nucleotide-based covalent inhibitors

Goebel

Kirschner

Koska

et al. 2022

Preprint

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“…The rate at which this happens is limited by the slow conversion of mutant KRAS G12C -GTP to KRAS G12C -GDP, to which the drug binds, although other factors may impact this in vivo. For example, Li et al 20 recently showed that, in some cancer cells, the proportion of KRAS G12C in the inactive form may be higher than expected because other cellular enzymes of the regulator of G proteins family happen to convert the active form of KRAS G12C -GTP to the GDP form by an off-target GTPase-activating protein mechanism.…”

Section: Practical Applicationsmentioning

confidence: 99%

More to the RAS Story: KRAS^G12C Inhibition, Resistance Mechanisms, and Moving Beyond KRAS^G12C

Lietman

Johnson

McCormick

et al. 2022

American Society of Clinical Oncology Educational Book

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Despite the discovery of RAS oncogenes in human tumor DNA 40 years ago, the development of effective targeted therapies directed against RAS has lagged behind those more successful advancements in the field of therapeutic tyrosine kinase inhibitors targeting other oncogenes such as EGFR, ALK, and ROS1. The discoveries that (1) malignant RAS oncogenes differ from their wild-type counterparts by only a single amino acid change and (2) covalent inhibition of the cysteine residue at codon 12 of KRASG12C in its inactive GDP-bound state resulted in effective inhibition of oncogenic RAS signaling and have catalyzed a dramatic shift in mindset toward KRAS-driven cancers. Although the development of allele-selective KRASG12C inhibitors has changed a treatment paradigm, the clinical activity of these agents is more modest than tyrosine kinase inhibitors targeting other oncogene-driven cancers. Heterogeneous resistance mechanisms generally result in the restoration of RAS/mitogen-activated protein kinase pathway signaling. Many approaches are being evaluated to overcome this resistance, with many combinatorial clinical trials ongoing. Furthermore, because KRASG12D and KRASG12V are more prevalent than KRASG12C, there remains an unmet need for additional therapeutic strategies for these patients. Thus, our current translational standing could be described as “the end of the beginning,” with additional discovery and research innovation needed to address the enormous disease burden imposed by RAS-mutant cancers. Here, we describe the development of KRASG12C inhibitors, the challenges of resistance to these inhibitors, strategies to mitigate that resistance, and new approaches being taken to address other RAS-mutant cancers.

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“…A remaining barrier is the genotype specificity of current clinically available inhibitors, as G12C mutations account for nearly half (46%) of mutations in NSCLC [ 7 ] but only 4–14% of KRAS mutations in all human cancers [ 33 ]. One of the unique features of the KRAS G12C mutant is its retention of near wild type intrinsic GTPase activity, allowing covalent inhibitors to selectively target the inactive GDP state and retain high efficacy [ 34 ]. In contrast, the KRAS G12D mutant demonstrates a high nucleotide exchange rate.…”

Section: Strategies To Target Oncogenic Mutant Krasmentioning

confidence: 99%

Synthetic Vulnerabilities in the KRAS Pathway

Román

Hwang

Sweet-Cordero

2022

Cancers

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Mutations in Kristen Rat Sarcoma viral oncogene (KRAS) are among the most frequent gain-of-function genetic alterations in human cancer. Most KRAS-driven cancers depend on its sustained expression and signaling. Despite spectacular recent success in the development of inhibitors targeting specific KRAS alleles, the discovery and utilization of effective directed therapies for KRAS-mutant cancers remains a major unmet need. One potential approach is the identification of KRAS-specific synthetic lethal vulnerabilities. For example, while KRAS-driven oncogenesis requires the activation of a number of signaling pathways, it also triggers stress response pathways in cancer cells that could potentially be targeted for therapeutic benefit. This review will discuss how the latest advances in functional genomics and the development of more refined models have demonstrated the existence of molecular pathways that can be exploited to uncover synthetic lethal interactions with a promising future as potential clinical treatments in KRAS-mutant cancers.

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The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS

Cited by 49 publications

References 37 publications

Targeting oncogenic KRasG13C with nucleotide-based covalent inhibitors

Targeting oncogenic KRasG13C with nucleotide-based covalent inhibitors

More to the RAS Story: KRAS^G12C Inhibition, Resistance Mechanisms, and Moving Beyond KRAS^G12C

Synthetic Vulnerabilities in the KRAS Pathway

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The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS

Cited by 49 publications

References 37 publications

Targeting oncogenic KRasG13C with nucleotide-based covalent inhibitors

Targeting oncogenic KRasG13C with nucleotide-based covalent inhibitors

More to the RAS Story: KRASG12C Inhibition, Resistance Mechanisms, and Moving Beyond KRASG12C

Synthetic Vulnerabilities in the KRAS Pathway

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More to the RAS Story: KRAS^G12C Inhibition, Resistance Mechanisms, and Moving Beyond KRAS^G12C