An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Karoulia, Zoi; Wu, Yang; Ahmed, Tamer A.; Xin, Qisheng; Bollard, Julien; Krepler, Clemens; Wu, Xuewei; Zhang, Chao; Bollag, Gideon; Herlyn, Meenhard; Fagin, James A.; Lujambio, Amaia; Gavathiotis, Evripidis; Poulikakos, Poulikos I.

doi:10.1016/j.ccell.2016.06.024

Cited by 155 publications

(250 citation statements)

References 46 publications

Supporting

Mentioning

235

Contrasting

Order By: Relevance

“…The active conformation in RAF is facilitated by dimerization. Dimerized RAF has been visualized by several crystal structures determined with BRAF or CRAF bound to inhibitors, providing insights into the dimerization interface 10,30,47-50 . The dimerization interface of each BRAF protomer includes the αC-helix of each kinase and specifically the interaction between the C-terminal R509 residue of each αC-helix.…”

Section: Structural Insight Into Raf Activationmentioning

confidence: 99%

“…Recently, two crystal structures of monomeric BRAF kinase bound to structurally related compounds 30,54 and the crystal structure of the BRAF–MEK complex 55 have been determined, thereby providing important insight on the conformational transitions and the structural basis of dimerization-dependent RAF activation. The structure of monomeric BRAF shows the kinase in an inactive conformation characterized by an open configuration between the N-lobe and C-lobe of the kinase domain 30,54 .…”

Section: Structural Insight Into Raf Activationmentioning

confidence: 99%

“…The structure of monomeric BRAF shows the kinase in an inactive conformation characterized by an open configuration between the N-lobe and C-lobe of the kinase domain 30,54 . The αC-helix is positioned in the OUT position, where it is stabilized by interactions with residues of the folded activation segment, which has also been determined 30,54 (FIG. 1c).…”

Section: Structural Insight Into Raf Activationmentioning

confidence: 99%

“…In this conformation, the position of the αC-helix is shifted to the full IN position, and the activation segment is extended as an unstructured loop that enables the shift of the αC-helix to facilitate catalysis and the interaction with the substrate 55 . The crystal structures show the DFG motif to adopt an IN conformation in both the active and the inactive kinase conformations 30,55 (FIG. 1b,c).…”

Section: Structural Insight Into Raf Activationmentioning

confidence: 99%

“…Recent studies suggested the importance of a salt bridge between V600E in the activation segment and K507 of the αC-helix in stabilizing the active conformation of BRAF-V600E as evidenced by crystal structures of the BRAF-V600E dimer 54,55 . However, cell-based and biochemical data established that BRAF-V600 proteins in the presence of low levels of RAS-GTP can be catalytically active monomers 30,31,51-53,56 . The reason for this discrepancy is presumably the absence of the N-terminal regulatory domain of BRAF in available crystal structures; this domain may be involved in the stabilization of an active monomeric conformation of V600-mutant BRAF kinase.…”

Section: Structural Insight Into Raf Activationmentioning

confidence: 99%

See 4 more Smart Citations

New perspectives for targeting RAF kinase in human cancer

2017

Self Cite

View full text Add to dashboard Cite

The discovery that a subset of human tumours is dependent on mutationally deregulated BRAF kinase intensified the development of RAF inhibitors to be used as potential therapeutics. The US Food and Drug Administration (FDA)-approved second-generation RAF inhibitors vemurafenib and dabrafenib have elicited remarkable responses and improved survival of patients with BRAF-V600E/K melanoma, but their effectiveness is limited by resistance. Beyond melanoma, current clinical RAF inhibitors show modest efficacy when used for colorectal and thyroid BRAF-V600E tumours or for tumours harbouring BRAF alterations other than the V600 mutation. Accumulated experimental and clinical evidence indicates that the complex biochemical mechanisms of RAF kinase signalling account both for the effectiveness of RAF inhibitors and for the various mechanisms of tumour resistance to them. Recently, a number of next-generation RAF inhibitors, with diverse structural and biochemical properties, have entered preclinical and clinical development. In this Review, we discuss the current understanding of RAF kinase regulation, mechanisms of inhibitor action and related clinical resistance to these drugs. The recent elucidation of critical structural and biochemical aspects of RAF inhibitor action, combined with the availability of a number of structurally diverse RAF inhibitors currently in preclinical and clinical development, will enable the design of more effective RAF inhibitors and RAF-inhibitor-based therapeutic strategies, tailored to different clinical contexts.

show abstract

Section: Structural Insight Into Raf Activationmentioning

confidence: 99%

Section: Structural Insight Into Raf Activationmentioning

confidence: 99%

Section: Structural Insight Into Raf Activationmentioning

confidence: 99%

Section: Structural Insight Into Raf Activationmentioning

confidence: 99%

Section: Structural Insight Into Raf Activationmentioning

confidence: 99%

See 3 more Smart Citations

New perspectives for targeting RAF kinase in human cancer

2017

Self Cite

View full text Add to dashboard Cite

show abstract

RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumors

Yuan

Tang

et al. 2020

Molecular Oncology

View full text Add to dashboard Cite

The mutation of K-RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K-RAS mutations. The reduced sensitivity of K-RAS-mutated cells to certain MEK inhibitors (MEKi) is associated with the feedback phosphorylation of MEK by C-RAF and with the reactivation of mitogen-activated protein kinase (MAPK) signaling. Here, we report that the RAF dimer inhibitors lifirafenib (BGB-283) and compound C show a strong synergistic effect with MEKi, including mirdametinib (PD-0325901) and selumetinib, in suppressing the proliferation of K-RAS-mutated non-small-cell lung cancer and colorectal cancer (CRC) cell lines. This synergistic effect was not observed with the B-RAF V600E selective inhibitor vemurafenib. Our mechanistic analysis revealed that RAF dimer inhibition suppresses RAF-dependent MEK reactivation and leads to the sustained inhibition of MAPK signaling in K-RAS-mutated cells. This synergistic effect was also observed in several K-RAS mutant mouse xenograft models. A pharmacodynamic analysis supported a role for the synergistic phospho-ERK blockade in enhancing the antitumor activity observed in the K-RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K-RAS-mutated cancers, and have led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K-RAS mutations and other MAPK pathway aberrations.Abbreviations CR, complete regression; CRC, colorectal cancer; EOHSA, excess over highest single agent; MAPK, mitogen-activated protein kinase; MEKi, MEK inhibitors; NFA, negative feedback amplified; NSCLC, non-small-cell lung cancer; PR, partial regression; TGI, tumor growth inhibition; WT, wild-type.

show abstract

Novel RAF‐directed approaches to overcome current clinical limits and block the RAS/RAF node

Scardaci,

Berlinska,

Scaparone

et al. 2024

Molecular Oncology

View full text Add to dashboard Cite

Mutations in the RAS–RAF–MEK–ERK pathway are frequent alterations in cancer and RASopathies, and while RAS oncogene activation alone affects 19% of all patients and accounts for approximately 3.4 million new cases every year, less frequent alterations in the cascade's downstream effectors are also involved in cancer etiology. RAS proteins initiate the signaling cascade by promoting the dimerization of RAF kinases, which can act as oncoproteins as well: BRAFV600E is the most common oncogenic driver, mutated in the 8% of all malignancies. Research in this field led to the development of drugs that target the BRAFV600‐like mutations (Class I), which are now utilized in clinics, but cause paradoxical activation of the pathway and resistance development. Furthermore, they are ineffective against non‐BRAFV600E malignancies that dimerize and could be either RTK/RAS independent or dependent (Class II and III, respectively), which are still lacking an effective treatment. This review discusses the recent advances in anti‐RAF therapies, including paradox breakers, dimer‐inhibitors, immunotherapies, and other novel approaches, critically evaluating their efficacy in overcoming the therapeutic limitations, and their putative role in blocking the RAS pathway.

show abstract

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Cited by 155 publications

References 46 publications

New perspectives for targeting RAF kinase in human cancer

New perspectives for targeting RAF kinase in human cancer

RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumors

Novel RAF‐directed approaches to overcome current clinical limits and block the RAS/RAF node

Contact Info

Product

Resources

About