Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma

Girotti, María Romina; Lopes, Filipa; Preece, Natasha; Niculescu‐Duvaz, Dan; Zambon, Alfonso; Davies, Lawrence; Whittaker, Steven R.; Saturno, Grazia; Virós, Amaya; Pedersen, Malin; Suijkerbuijk, Bart M. J. M.; Ménard, Delphine; McLeary, Robert; Johnson, Linda Y; Fish, Laura J.; Ejiama, Sarah; Sánchez-Laorden, Berta; Hohloch, Juliane; Carragher, Neil O.; Macleod, Kenneth; Ashton, Garry; Marusiak, Anna A.; Fusi, Alberto; Brognard, John; Frame, Margaret C.; Lorigan, Paul; Marais, Richard; Springer, Caroline J.

doi:10.1016/j.ccell.2014.11.006

Cited by 175 publications

(103 citation statements)

References 39 publications

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“…They further concluded that these somatic mutations accounted for more cancer cases than either inherited genetic disease or specific environmental risk factors. These observations are also consistent with the idea that cancer is essentially a disease of “stemness” gone awry [7, 8]. …”

Section: Introductionsupporting

confidence: 88%

Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease

et al. 2015

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Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of “stemness”, independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point – a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known “side-effect”, which could be harnessed instead as a “therapeutic effect”. Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.

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Section: Introductionsupporting

confidence: 88%

Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease

et al. 2015

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“…Because CRAF signals as an obligatory dimer 50,65 , αC-OUT inhibitors fail to suppress its activity. Thus, αC-IN RAF inhibitors, by suppressing both BRAF and CRAF dimers can also be considered ‘pan-RAF inhibitors’ 66-68 and may be effective when used in combination in contexts such as RAS-mutant tumour cells, in which CRAF is known to be a major activator of ERK signalling downstream of RAS. However, a potentially narrow therapeutic window and allosteric priming (see below) are predicted to limit the effectiveness of αC-IN RAF inhibitor monotherapy in RAS-mutant tumours 30 .…”

Section: Models Of Raf Inhibitor Actionmentioning

confidence: 99%

“…CCT196969 and CCT241161 have been reported as dual pan-RAF and SRC kinase inhibitors 66 . Although crystallographic data are not available, these compounds behave biochemically in a similar manner to αC-IN RAF inhibitors.…”

Section: Development Of Raf Inhibitorsmentioning

confidence: 99%

New perspectives for targeting RAF kinase in human cancer

2017

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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.

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“…Several BRAF inhibitors enhance BRAF dimerisation in a RAS-dependent manner thereby activating MAPK signalling [62]. Novel inhibitors are being developed to evade this phenomenon [69,70]. RAF dimers are functionally asymmetrical [71] with one RAF kinase functioning as an activator to stimulate activity of the second RAF kinase (receiver, Figure 3).…”

Section: Raf Dimerisationmentioning

confidence: 98%

The complexities and versatility of the RAS-to-ERK signalling system in normal and cancer cells

Fey

Matallanas

Rauch

et al. 2016

Seminars in Cell & Developmental Biology

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The intricate dynamic control and plasticity of RAS to ERK mitogenic, survival and apoptotic signalling has mystified researches for more than 30 years. Therapeutics targeting the oncogenic aberrations within this pathway often yield unsatisfactory, even undesired results, as in the case of paradoxical ERK activation in response to RAF inhibition. A direct approach of inhibiting single oncogenic proteins misses the dynamic network context governing the network signal processing. In this review, we discuss the signalling behaviour of RAS and RAF proteins in normal and in cancer cells, and the emerging systems-level properties of the RAS-to-ERK signalling network. We argue that to understand the dynamic complexities of this control system, mathematical models including mechanistic detail are required. Looking into the future, these dynamic models will build the foundation upon which more effective, rational approaches to cancer therapy will be developed.

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Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma

Cited by 175 publications

References 39 publications

Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease

Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease

New perspectives for targeting RAF kinase in human cancer

The complexities and versatility of the RAS-to-ERK signalling system in normal and cancer cells

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