Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling

Rukhlenko, Oleksii S.; Khorsand, Fahimeh; Krstić, Aleksandar; Rožanc, Jan; Alexopoulos, Leonidas G.; Rauch, Nora; Erickson, Keesha E.; Hlavacek, William S.; Posner, Richard G.; Gómez‐Coca, Silvia; Rosta, Edina; Fitzgibbon, Cheree; Matallanas, David; Rauch, Jens; Kölch, Walter; Kholodenko, Boris N.

doi:10.1016/j.cels.2018.06.002

Cited by 57 publications

(82 citation statements)

References 118 publications

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“…Overall, our mathematical analysis suggests that the conformational regulation of RAF kinase activity combined with inhibitor dependent dimerization is a critical mechanism that drives PA. Although autoinhibition has been recognized as an important component of the entire PA phenomenon (15,21) it appears to have been underappreciated as a mechanism capable of driving PA; for example, it has neither been discussed as a motivation for the development of third generation RAF inhibitors (3-5) nor been included in recent mathematical analyses of PA (40,45). This is notable, as both drug development and mathematical analyses pay considerable attention to conformations within the kinase domain (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Other processes, like negative allostery (or negative cooperativity) for inhibitor binding (18), preferential binding to the different RAF proteins and/or mutant RAF (2), altered dimerization affinity for drug-bound RAF proteins (20,40,45), phosphorylation changes (28), scaffold proteins (29), allosteric trans-activation (24), and Ras nanoclusters (31) may all further tune the response to inhibitor, including in drug-specific manners.…”

Section: Discussionmentioning

confidence: 99%

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RAF conformational autoinhibition and 14-3-3 proteins promote paradoxical activation

Mendiratta

Abbott

et al. 2019

Preprint

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RAF kinase inhibitors can actually increase RAF kinase signaling. This process, which is commonly referred to as "paradoxical activation" (PA), is incompletely understood. RAF kinases are regulated by autoinhibitory conformational changes, and the role of these conformational changes in PA is unclear. Our mathematical investigations find that PA can result from a dynamical equilibrium between autoinhibited and non-autoinhibited forms of RAF, along with the RAF inhibitor stabilizing the non-autoinhibited form. We also investigate whether PA is influenced by 14-3-3 proteins, which can both stabilize RAF autoinhibition and RAF dimerization. Using both computational and experimental methods we demonstrate that 14-3-3 proteins potentiate PA. Third generation RAF inhibitors normally display minimal to no PA. Our mathematical modeling led us to hypothesize that increased 14-3-3 expression should also amplify PA for these agents. Subsequent experiments support our hypothesis and show that 14-3-3 overexpression increases PA in these third generation RAF inhibitors, effectively "breaking" these "paradox breakers" and pan-RAF inhibitors. We have therefore created and experimentally validated a robust mechanism for PA based solely on equilibrium dynamics of canonical interactions in RAF signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

RAF conformational autoinhibition and 14-3-3 proteins promote paradoxical activation

Mendiratta

Abbott

et al. 2019

Preprint

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“…Its molecular structure comprises three conserved regions: Conserved region (CR) l (located at aa , CR2 (located at aa 254-269) and CR3 (located at aa 335-627). CRl, located at the amino terminus, is rich in cysteine and contains a zinc finger-like structure, similar to the ligand-binding region of PKC (45). CR1 is the main site of activated Ras binding to Raf-1 protein kinase.…”

Section: Erk/mapk Structure and Functionsmentioning

confidence: 99%

ERK/MAPK signalling pathway and tumorigenesis (Review)

et al. 2020

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Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised. signalling elements that regulate basic processes including cell proliferation, differentiation and stress responses (1-3). These cascades transmit signals through sequential activation of three to five layers of protein kinases known as MAPK kinase kinase kinase (MAP4K), MAPK kinase kinase (MAP3K), MAPK kinase (MAPKK), MAPK and MAPK-activated protein kinases (MAPKAPK). The first three central layers are considered as a basic core unit, while the last two layers appear in some cascades and can vary among cells and stimuli. Four MAPK cascades have been defined based on the components in the MAPK layer: ERK1/2, c-Jun N-terminal kinase (JNK), p38 MAPK and ERK5. This review focuses on the ERK cascade (4-6) which involves several kinases in the MAP3K layer (mainly Rafs), including Ras/Raf/MAPK (MEK) 1/2 at the MAPKK layer, ERK1/2 at the MAPK layer and several MAPKAPKs in the next layer (ribosomal s6 kinases, MAP kinase-interacting serine/threonine-protein kinases, mitogen-and stress-activated protein kinases and cytosolic phospholipase A2). ERK cascades are highly regulated cascades that are responsible for basic cellular processes, including cell proliferation and differentiation. These regulatory factors affect bispecific phosphatases (7-10), scaffold proteins (11-14), signal duration and intensity (15), and the dynamic subcellular localization of cascade components (16,17). Due to the importance of the ERK cascade, ERK disorders are harmful to cells and ultimately to the body. Excessive activation of upstream proteins and kinases in the ERK pathway has been shown to induce various diseases, including cancer, inflammation, developmental disorders and neurological disorders (18-22). Since ERK1 and ERK2 are very similar, the singular form of ERK is used in this review, although two subtypes exist. Dysfunction in the Ras-ERK pat...

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“…This type of resistance can be broken by RAF inhibitors that prevent dimerization [56], or by a combination of two structurally different RAF inhibitors that target the two different conformations of RAF proteins in a dimer. For the latter approach, Kholodenko and colleagues developed a new mathematical model that considers the genetic mutational background, network context, thermodynamic parameters, and post-translational modifications and can accurately predict which type of inhibitors should be combined [57]. Table 1.…”

Section: Mechanisms Of Drug Resistance In the Erk Pathwaymentioning

confidence: 99%

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Lee

Rauch

Kölch

2020

IJMS

Self Cite

436

288

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Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.

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Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling

Cited by 57 publications

References 118 publications

RAF conformational autoinhibition and 14-3-3 proteins promote paradoxical activation

RAF conformational autoinhibition and 14-3-3 proteins promote paradoxical activation

ERK/MAPK signalling pathway and tumorigenesis (Review)

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

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