BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers

Sanchez, Jaquelyn; Ton, Wang; Cohen, Mark S.

doi:10.1007/s40265-018-0884-8

Cited by 99 publications

(80 citation statements)

References 114 publications

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“…There, the prevalent escape routes are adaptive network responses that result in the revival of ERK activation or the recruitment of other pathways that can substitute for ERK activity (Figure 3). Although a main mechanism of resistance to RAF or MEK inhibitors is reactivation of ERK signaling [18][19][20], resistance mechanisms to combined RAF and MEK inhibition increasingly include the activation of alternative pathways that can drive cancer cell proliferation and survival [21,22]. The resistance mechanisms to clinically used inhibitors that block ERK signaling are summarized in 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

489

338

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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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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

489

338

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“…BRAF (v-raf murine sarcoma viral oncogene homolog B) encodes for a protein kinase acting through the MAP (mitogen-activated protein) kinase cascade, playing an important role in cell proliferation, differentiation and survival [6]. Given its pivotal location in many neoplastic-related dysregulated pathways, it easily explains its oncogenic role in many human malignancies, including melanoma, ovarian carcinoma, papillary thyroid carcinoma and CRC [7,8]. Of note, the oncogenic contribution of mutated BRAF gene varies between cancer types, justifying significant differences in clinico-pathological features, prognostic impact and therapy response among various malignancies [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…By the pathological point of view, BRAFmt CRCs are characterized by more aggressive pathological features like high grade and peritoneal dissemination and they present in an advanced stage at the time of the initial diagnosis. Furthermore, BRAFmt mCRC patients usually develop an early resistance to standard and targetedtherapy, and only about an half of these patients can receive a second line chemotherapy, suggesting that more aggressive and individualized combined therapies may be effective in selected patients cohorts [7,15,[19][20][21][22][23][24]. Nevertheless, BRAF treatment-predictive value still remains a matter of debate.…”

Section: Introductionmentioning

confidence: 99%

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

et al. 2020

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Colorectal cancer (CRC) is a complex and molecularly heterogeneous disease representing one of the most frequent causes of cancer-related death worldwide. About 8-15% of CRCs harbor a mutation in BRAF gene, a proto-oncogene involved in cell proliferation, differentiation and survival through the MAPK signaling cascade. The acquisition of BRAF mutation is an early event in the "serrated" CRC carcinogenetic pathway and is associated with specific and aggressive clinico-pathological and molecular features. Despite that the presence of BRAF mutation is a well-recognized negative prognostic biomarker in metastatic CRC (mCRC), a great heterogeneity in survival outcome characterizes these patients, due to the complex, and still not completely fully elucidated, interactions between the clinical, genetic and epigenetic landscape of BRAF mutations. Because of the great aggressiveness of BRAF-mutated mCRCs, only 60% of patients can receive a second-line chemotherapy; so intensive combined and tailored first-line approach could be a potentially effective strategy, but to minimize the selective pressure of resistant clones and to reduce side effects, a better stratification of patients bearing BRAF mutations is needed.

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“…The cytoplasmic receptor is indicated by a thick black arrow. Adapted from(78,79). SOS, son of sevenless; GRB2, growth factor receptor-binding protein 2; p, phosphorylated.…”

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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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BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers

Cited by 99 publications

References 114 publications

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

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

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

ERK/MAPK signalling pathway and tumorigenesis (Review)

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