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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models

Authors: Anais Del Curatolo, Fabiana Conciatori, Ursula Cesta Incani, Chiara Bazzichetto, Italia Falcone, Vincenzo Corbo, Sabrina D’Agosto, Adriana Eramo, Giovanni Sette, Isabella Sperduti, Teresa De Luca, Mirko Marabese, Senji Shirasawa, Ruggero De Maria, Aldo Scarpa, Massimo Broggini, Donatella Del Bufalo, Francesco Cognetti, Michele Milella, Ludovica Ciuffreda

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

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Abstract

Background

Mounting evidence suggests that RAF-mediated MEK activation plays a crucial role in paradox MAPK (re)activation, leading to resistance and therapeutic failure with agents hitting a single step along the MAPK cascade.

Methods

We examined the molecular and functional effects of single and combined BRAF (dabrafenib), pan-RAF (RAF265), MEK (trametinib) and EGFR/HER2 (lapatinib) inhibition, using Western Blot and conservative isobologram analysis to assess functional synergism, and explored genetic determinants of synergistic interactions. Immunoprecipitation based assays were used to detect the interaction between BRAF and CRAF. The Mann-Whitney U test was used for comparing quantitative variables.

Results

Here we demonstrated that a combination of MEK and BRAF inhibitors overcomes paradoxical MAPK activation (induced by BRAF inhibitors) in BRAF-wt/RAS-mut NSCLC and PDAC in vitro. This results in growth inhibitory synergism, both in vitro and in vivo, in the majority (65%) of the cellular models analyzed, encompassing cell lines and patient-derived cancer stem cells and organoids. However, RAS mutational status is not the sole determinant of functional synergism between RAF and MEK inhibitors, as demonstrated in KRAS isogenic tumor cell line models. Moreover, in EGFR-driven contexts, paradoxical MAPK (re)activation in response to selective BRAF inhibition was dependent on EGFR family signaling and could be offset by simultaneous EGFR/HER-2 blockade.

Conclusions

Overall, our data indicate that RAF inhibition-induced paradoxical MAPK activation could be exploited for therapeutic purposes by simultaneously targeting both RAF and MEK (and potentially EGFR family members) in appropriate molecular contexts. KRAS mutation per se does not effectively predict therapeutic synergism and other biomarkers need to be developed to identify patients potentially deriving benefit from combined BRAF/MEK targeting.
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Metadata
Title
Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models
Authors
Anais Del Curatolo
Fabiana Conciatori
Ursula Cesta Incani
Chiara Bazzichetto
Italia Falcone
Vincenzo Corbo
Sabrina D’Agosto
Adriana Eramo
Giovanni Sette
Isabella Sperduti
Teresa De Luca
Mirko Marabese
Senji Shirasawa
Ruggero De Maria
Aldo Scarpa
Massimo Broggini
Donatella Del Bufalo
Francesco Cognetti
Michele Milella
Ludovica Ciuffreda
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0820-5

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