New <i>RAS</i>-Mutant Pancreatic Adenocarcinoma With Combined BRAF and MEK Inhibition for Metastatic Melanoma

Carlino, Matteo S.; Kwan, Vu; Miller, David; Saunders, Catherine A.B.; Yip, Desmond; Nagrial, Adnan; Tomlinson, Jeanne; Grimmond, Sean M.; Scolyer, Richard A.; Kefford, Richard; Biankin, Andrew V.; Long, Georgina V.

doi:10.1200/jco.2013.51.5783

Cited by 30 publications

(20 citation statements)

References 16 publications

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“…Combining the RAF inhibitor with the MEK inhibitor cobimetinib (GDC-0973; Genentech) led to simultaneous suppression of both the melanoma and RAF-inhibitor-induced leukaemia 60 . More recently, a previously unsuspected RAS-mutant pancreatic adenocarcinoma was detected in a patient with melanoma who had been treated with a combination of dabrafenib and trametinib 61 .…”

Section: Mek Inhibitorsmentioning

confidence: 98%

Targeting RAS–ERK signalling in cancer: promises and challenges

Samatar¹,

Poulikakos

2014

Nat Rev Drug Discov

958

801

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The RAS-RAF-MEK-ERK signalling pathway is hyperactivated in a high percentage of tumours, most frequently owing to activating mutations of the KRAS, NRAS and BRAF genes. Recently, the use of compounds targeting components of ERK signalling, such as RAF or MEK inhibitors, has led to substantial improvement in clinical outcome in metastatic melanoma and has shown promising clinical activity in additional tumour types. However, response rates are highly variable and the efficacy of these drugs is primarily limited by the development of resistance. Both intrinsic and acquired resistance to RAF and MEK inhibitors are frequently associated with the persistence of ERK signalling in the presence of the drug, implying the need for more innovative approaches to target the pathway.

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Section: Mek Inhibitorsmentioning

confidence: 98%

Targeting RAS–ERK signalling in cancer: promises and challenges

Samatar¹,

Poulikakos

2014

Nat Rev Drug Discov

958

801

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“…In contrast to their efficacy in BRAF -mutant cancers, vemurafenib and dabrafenib not only are ineffective in RAS -mutant cancers, but instead stimulate their growth [33-37] . This effect is due to paradoxical activation of ERK, rather than inhibition.…”

Section: Raf Inhibitorsmentioning

confidence: 99%

Targeting RAS -mutant Cancers: Is ERK the Key?

et al. 2015

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The three RAS genes comprise the most frequently mutated oncogene family in cancer. With significant and compelling evidence that continued function of mutant RAS is required for tumor maintenance, it is widely accepted that effective anti-RAS therapy will have a significant impact on cancer growth and patient survival. However, despite more than three decades of intense research and pharmaceutical industry efforts, a clinically effective anti-RAS drug has yet to be developed. With the recent renewed interest in targeting RAS, exciting and promising progress has been made. In this review, we discuss the prospects and challenges of drugging oncogenic RAS. In particular we focus on new inhibitors of RAS effector signaling and the ERK mitogen-activated protein kinase cascade.

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“…This paradoxical ERK activation underlies the occurrence of keratoacanthomas, squamous cell carcinomas, and even de novo melanomas in the context of RAF inhibitor treatment (6,7). Compatible with the concept that increased RAS signaling mediates paradoxical ERK activation under BRAF inhibition, activating mutations in RAS genes were found in the majority of cutaneous squamous lesions (8), as secondary events in previously vemurafenib-responsive BRAF mutant melanoma (9), in a chronic myelomonocytic leukemia (CMML) (10), and in a pancreatic carcinoma (11) progressing under BRAF inhibition. Overexpression, mutation, and microenvironment-mediated hyperactivation of RTKs were identified as drug-resistance mechanisms in melanoma.…”

Section: Introductionmentioning

confidence: 98%