Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects

Marcus, Kendra; Mattos, Carla

doi:10.1158/1078-0432.ccr-14-2148

Cited by 75 publications

(80 citation statements)

References 90 publications

(128 reference statements)

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“…Early direct approaches sought to attack this impaired molecular switch. Attempts to identify antagonists of GTP-binding or to identify drug-like mimics of the negative regulatory GAP proteins have been unsuccessful, although new strategies of stabilizing conformational states may yet bear fruit, as discussed elsewhere in this CCR Focus section (3). More recent efforts to target specific RAS mutations (e.g., KRAS G12C), to interfere with RAS binding to its activator SOS1, and to block association with effectors such as RAF1 have been reviewed recently (1,4).…”

Section: Introductionmentioning

confidence: 99%

Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Cox

Der

Philips

2015

Clinical Cancer Research

323

292

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RAS proteins require membrane association for their biological activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTIs) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anti-cancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated post-translational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development.

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Section: Introductionmentioning

confidence: 99%

Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Cox

Der

Philips

2015

Clinical Cancer Research

323

292

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“…K-Ras dynamics in different conformational states, that can also change due to allosteric interactions between protein residues, also need to be quantified22. However, we still need to clearly understand the intra-molecular allosteric networks between distant sites on K-Ras23. While such allosteric interaction sites have recently been discovered in its catalytic domain242526, they remain largely understudied23.…”

mentioning

confidence: 99%

Intrinsic K-Ras dynamics: A novel molecular dynamics data analysis method shows causality between residue pair motions

Gümüş

Erman

2016

Sci Rep

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K-Ras is the most frequently mutated oncogene in human cancers, but there are still no drugs that directly target it in the clinic. Recent studies utilizing dynamics information show promising results for selectively targeting mutant K-Ras. However, despite extensive characterization, the mechanisms by which K-Ras residue fluctuations transfer allosteric regulatory information remain unknown. Understanding the direction of information flow can provide new mechanistic insights for K-Ras targeting. Here, we present a novel approach –conditional time-delayed correlations (CTC) – using the motions of all residue pairs of a protein to predict directionality in the allosteric regulation of the protein fluctuations. Analyzing nucleotide-dependent intrinsic K-Ras motions with the new approach yields predictions that agree with the literature, showing that GTP-binding stabilizes K-Ras motions and leads to residue correlations with relatively long characteristic decay times. Furthermore, our study is the first to identify driver-follower relationships in correlated motions of K-Ras residue pairs, revealing the direction of information flow during allosteric modulation of its nucleotide-dependent intrinsic activity: active K-Ras Switch-II region motions drive Switch-I region motions, while α-helix-3L7 motions control both. Our results provide novel insights for strategies that directly target mutant K-Ras.

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“…6 Inhibitors of KRAS processing/ membrane association, and disruption of interaction with chaperones that transfer KRAS to and from the cell membrane have also been investigated. 7 However, despite these efforts, agents directly targeting KRAS have been of limited clinical utility.…”

Section: Therapeutic Targeting Of Kras Ladcmentioning

confidence: 99%

Targeting oncogenic protein kinase Cι for treatment of mutantKRASLADC

et al. 2016

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Lung cancer is the leading cause of cancer death in the US with »124,000 new cases annually, and a 5 y survival rate of »16%. Mutant KRAS-driven lung adenocarcinoma (KRAS LADC) is a particularly prevalent and deadly form of lung cancer. Protein kinase Ci (PKCi) is an oncogenic effector of KRAS that activates multiple signaling pathways that stimulate transformed growth and invasion, and maintain a KRAS LADC tumor-initiating cell (TIC) phenotype. PKCi inhibitors used alone and in strategic combination show promise as new therapeutic approaches to treatment of KRAS LADC. These novel drug combinations may improve clinical management of KRAS LADC.KEYWORDS lung adenocarcinoma; oncogenic Kras; Protein Kinase Ciota; therapeutic targeting KRAS mutation is an oncogenic driver required for LADC tumor initiation and maintenance Activating KRAS mutations are detected in approximately 33% of LADC. KRAS mutations are also present in preneoplastic lesions of the lung (atypical alveolar hyperplasias, AAH), suggesting early acquisition during lung neoplasia.1 Genomic sequencing of lung adenomas in situ revealed both regional histological and genomic heterogeneity; however, KRAS mutations were observed uniformly throughout individual lesions, indicating that mutant KRAS drives early tumor cell transformation, selection and evolution. 2Expression of mutant KrasG12D in the mouse lung is sufficient to drive LADC initiation, providing in vivo evidence that KRAS is a key oncogenic driver of LADC initiation.3,4 Interestingly, systemic delivery of KRAS siRNA significantly inhibited tumor growth and metastasis of mutant KRAS LADC tumors, demonstrating a continued dependency on mutant KRAS signaling for tumor maintenance.

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Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects

Cited by 75 publications

References 90 publications

Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Intrinsic K-Ras dynamics: A novel molecular dynamics data analysis method shows causality between residue pair motions

Targeting oncogenic protein kinase Cι for treatment of mutantKRASLADC

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