Secondary Tumors Arising in Patients Undergoing BRAF Inhibitor Therapy Exhibit Increased BRAF–CRAF Heterodimerization

Boussemart, Lise; Girault, Isabelle; Malka-Mahieu, Hélène; Mateus, Christine; Routier, Émilie; Rubington, Margot; Kamsu‐Kom, Nyam; Thomas, Marina; Tomasic, Gorana; Agoussi, Sandrine; Breckler, Marie; Laporte, Mélanie; Lacroix, Ludovic; Eggermont, Alexander M.M.; Cavalcanti, A.; Grange, Florent; Adam, Julien; Vagner, Stéphan; Robert, Caroline

doi:10.1158/0008-5472.can-15-2900-t

Cited by 43 publications

(26 citation statements)

References 31 publications

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“…These secondary cancers were subsequently found to be induced by the "paradoxical activation" of CRAF by BRAF inhibitors in pre-existing keratinocytic lesions harboring wild-type BRAF, but activated RAS (36,37). While clinically manageable, these discoveries prompted further studies, which found that indeed, BRAF inhibition can accelerate the development of pre-existing RAS mutant malignancies including NRAS mutant leukemias or K-RAS mutant pancreatic or colon adenocarcinomas (38)(39)(40)(41).…”

Section: Braf Inhibitors As Single Agentmentioning

confidence: 99%

Overcoming resistance to BRAF inhibitors

2017

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Abstract:The discovery of activating mutations in the serine/threonine (S/T) kinase BRAF followed by a wave of follow-up research manifested that the MAPK-pathway plays a critical role in melanoma initiation and progression. BRAF and MEK inhibitors produce an unparalleled response rate in melanoma, but it is now clear that most responses are transient, and while some patients show long lasting responses the majority progress within 1 year. In accordance with the key role played by the MAPK-pathway in BRAF mutant melanomas, disease progression is mostly due to the appearance of drug-resistance mechanisms leading to restoration of MAPK-pathway activity. In the present article we will review the development, application and clinical effects of BRAF and MEK inhibitors both, as single agent and in combination in the context of targeted therapy in melanoma. We will then describe the most prominent mechanisms of resistance found in patients progressed on these targeted therapies. Finally we will discuss strategies for further optimizing the use of MAPK inhibitors and will describe the potential of alternative combination therapies to either delay the onset of resistance to MAPK inhibitors or directly target specific mechanisms of resistance to BRAF/ MEK inhibitors.

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Section: Braf Inhibitors As Single Agentmentioning

confidence: 99%

Overcoming resistance to BRAF inhibitors

2017

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“…Even worse, BRAF inhibition could accelerate proliferation of RAS mutant cells. Secondary neoplasms have been reported to develop in human cancer patients treated with BRAF inhibitors . These secondary neoplasms are considered to arise through paradoxical MAPK pathway activation mediated by preexisting RAS mutations or activation of other signaling pathways in response to BRAF inhibition .…”

Section: Mutation Frequencies Of Hras Kras Nras and Braf Genes In Cmentioning

confidence: 99%

Sequence analysis ofRASandRAFmutation hot spots in canine carcinoma

Mochizuki

Breen

2016

Vet Comparative Oncology

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Recent discovery of the BRAF V595E mutation in a variety of canine cancers indicates that mutant BRAF may represent a novel therapeutic target. Presence of RAS mutations is associated with poor tumour response to BRAF inhibition but has not been investigated in BRAF-mutated canine cancers. The aim of this study was to evaluate the mutational status of three RAS genes (HRAS, KRAS and NRAS) in four types of canine carcinoma with and without the BRAF V595E mutation. Novel HRAS mutations were identified in 18% (3/17) of oral squamous cell carcinoma, whereas 17% (3/18) of pulmonary carcinoma carried KRAS or NRAS mutations. These RAS mutations and BRAF V595E were mutually exclusive, indicating similar functional consequence of these mutations (e.g. MAPK pathway activation). In contrast, RAS mutations were absent in 39 urothelial carcinoma and 19 prostatic carcinoma, adding another rational for BRAF-targeted therapy for these canine cancers.

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“…However, vemurafenib and other selective Braf inhibitors also amplify MAPK signaling downstream of oncogenic Kras or activated receptor tyrosine kinases (Hatzivassiliou et al, 2010; Heidorn et al, 2010; Poulikakos et al, 2010). This paradoxical effect promotes cell proliferation in experimental tumor models driven by oncogenic Ras and the onset of secondary RAS -driven malignancies in patients (Boussemart et al, 2016; Callahan et al, 2012; Su et al, 2012). Braf inhibitors thus represent an important but underutilized tool for studying the role of oncogenic MAPK signaling during tumor initiation and progression.…”

Section: Introductionmentioning

confidence: 99%

Context-Dependent Effects of Amplified MAPK Signaling during Lung Adenocarcinoma Initiation and Progression

et al. 2017

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SUMMARY Expression of oncogenic KrasG12D initiates lung adenomas in a MAPK signal-dependent manner from only a subset of cell types in the adult mouse lung. Amplification of MAPK signaling is associated with progression to malignant adenocarcinomas, but whether this is a cause or consequence of disease progression is not known. To better understand the effects of MAPK signaling downstream of KrasG12D expression, we capitalized on the ability of Braf inhibition to selectively amplify MAPK pathway signaling in KrasG12D-expressing epithelial cells. MAPK signal amplification indeed promoted the rapid progression of established adenomas to malignant adenocarcinomas. However, we surprisingly observed a greater number of overall tumor-initiating events after MAPK signal amplification, due to induced proliferation of cell types that are normally refractory to KrasG12D-induced transformation. Thus, MAPK signaling in the lung is thresholded not only during malignant progression, but also at the moment of tumor initiation.

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Secondary Tumors Arising in Patients Undergoing BRAF Inhibitor Therapy Exhibit Increased BRAF–CRAF Heterodimerization

Cited by 43 publications

References 31 publications

Overcoming resistance to BRAF inhibitors

Overcoming resistance to BRAF inhibitors

Sequence analysis ofRASandRAFmutation hot spots in canine carcinoma

Context-Dependent Effects of Amplified MAPK Signaling during Lung Adenocarcinoma Initiation and Progression

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