Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism

Lito, Piro; Solomon, Michelle; Li, Liansheng; Hansen, Rasmus; Rosen, Neal

doi:10.1126/science.aad6204

Cited by 526 publications

(548 citation statements)

References 37 publications

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“…2). Understanding additional mechanisms of KRAS independence will be critical for tailoring treatment decisions in future generations of KRAS inhibitors being developed by the RAS initiative at the National Cancer Institute (3)(4)(5). Moreover, because we used Kras G12D/+ ;p53 −/− mouse lung cancer cells, it remains unclear how additional genetic lesions (e.g., p53…”

Section: Discussionmentioning

confidence: 99%

“…KRAS is also frequently mutated in other tumor types, including pancreatic (>90%) and colon (∼30%) cancer (2). Although various pharmacological inhibitors are being developed for RAS, especially for the mutant KRAS G12C (3)(4)(5), these small molecules have not been tested in the clinic (6,7). As a result, advanced oncogenic KRAS lung cancers are usually treated with conventional therapy such as radiation and chemotherapy, often with limited success (1,8).…”

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confidence: 99%

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Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis

Mou

Moore

Malonia

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Genetic lesions that activate KRAS account for ∼30% of the 1.6 million annual cases of lung cancer. Despite clinical need, KRAS is still undruggable using traditional small-molecule drugs/inhibitors. When oncogenic Kras is suppressed by RNA interference, tumors initially regress but eventually recur and proliferate despite suppression of Kras. Here, we show that tumor cells can survive knockout of oncogenic Kras, indicating the existence of Kras-independent survival pathways. Thus, even if clinical KRAS inhibitors were available, resistance would remain an obstacle to treatment. Kras-independent cancer cells exhibit decreased colony formation in vitro but retain the ability to form tumors in mice. Comparing the transcriptomes of oncogenic Kras cells and Kras knockout cells, we identified 603 genes that were specifically up-regulated in Kras knockout cells, including the Fas gene, which encodes a cell surface death receptor involved in physiological regulation of apoptosis. Antibodies recognizing Fas receptor efficiently induced apoptosis of Kras knockout cells but not oncogenic Kras-expressing cells. Increased Fas expression in Kras knockout cells was attributed to decreased association of repressive epigenetic marks at the Fas promoter. Concordant with this observation, treating oncogenic Kras cells with histone deacetylase inhibitor and Fasactivating antibody efficiently induced apoptosis, thus bypassing the need to inhibit Kras. Our results suggest that activation of Fas could be exploited as an Achilles' heel in tumors initiated by oncogenic Kras.Kras | lung cancer | Fas | apoptosis

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis

Mou

Moore

Malonia

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Some recent investigations have generated a renewed interest in the development of direct KRAS inhibitors (19). For instance, Lito and colleagues (20) achieved blockade of nucleotide exchange factors from activating KRAS. They are working with a compound, ARS-853, which is a selective, covalent inhibitor of KRAS G12C that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation.…”

Section: Kras Mutations As a Predictive Factor Of Resistancementioning

confidence: 99%

KRAS mutations in the circulating free DNA (cfDNA) of non-small cell lung cancer (NSCLC) patients

Garzón¹,

Villatoro²,

Teixidó³

et al. 2016

Transl. Lung Cancer Res.

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“…G12 is the most frequently mutated residue (89%), which most prevalently mutates to aspartate (G12D, 36%) followed by valine (G12V, 23%) and cysteine (G12C, 14%) 3,10 . This residue is located at the protein active site, which consists of a phosphate binding loop (P-loop, residues 10-17) and switch I (SI, residues [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] and II (SII, residues 60-74) regions. The active site residues are bound to the phosphate groups of GTP and are responsible for the GTPase function of K-Ras.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic G12D mutation alters local conformations and dynamics of K-Ras

Erman

Gümüş

2017

Preprint

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K-Ras is the most frequently mutated protein in human tumors. Activating K-Ras mutations drive cancer initiation, progression and drug resistance, directly leading to nearly a million deaths per year. To understand the mechanisms by which mutations alter K-Ras function, we need to understand their effects on protein dynamics. However, despite decades of research, how oncogenic mutations in K-Ras alter its conformation and dynamics remain to be understood. Here, we present how the most recurrent K-Ras oncogenic mutation, G12D, leads to structural, conformational and dynamical changes that lead to constitutively active KRas. We have developed a new integrated MD simulation data analysis approach to quantify such changes in a protein and applied it to K-Ras. Our results show that G12D mutation induces strong negative correlations between the fluctuations of SII and those of the P-loop, Switch I (SI) and α3 regions in K-Ras G12D . Furthermore, characteristic decay times of SII fluctuations significantly increase after G12D mutation. We have further identified causal relationships between correlated residue pairs in K-Ras G12D and show that the correlated motions in K-Ras dynamics are driven by SII fluctuations, which have the strongest negative correlations with other protein parts and the longest characteristic decay times in mutant KRas. Ours is arguably the first study that shows the causal relationships between residue pairs in K-Ras G12D , relates them to the decay times and correlates their fluctuations.

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Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism

Cited by 526 publications

References 37 publications

Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis

Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis

KRAS mutations in the circulating free DNA (cfDNA) of non-small cell lung cancer (NSCLC) patients

Oncogenic G12D mutation alters local conformations and dynamics of K-Ras

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