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

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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

17 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)N/A-N/A
RivistaJOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume37
DOI
Stato di pubblicazionePubblicato - 2018

Keywords

  • BRAF
  • Cancer Research
  • Combination therapy
  • MAPK
  • MEK
  • Oncology
  • Paradoxical effect

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