Sensitivity to dabrafenib and trametinib treatments in patients with non-small-cell cancer harboring BRAF compound mutations: A pooled analysis of BRAF p.V600E-positive advanced non-small-cell lung cancer


      • The computational simulation model may be useful for predicting therapeutic effectiveness to BRAF compound mutations.
      • In addition to the generation of genomic information, the construction of a simulation database is important for establishing personalized medicine, helping prevent missing appropriate therapeutic opportunities in patients with druggable driver mutations.



      The present study clarified the sensitivity of the BRAF tyrosine kinase inhibitor mechanism in patients with BRAF compound mutation and predicted the sensitivity using molecular dynamics simulation.


      We examined 16 BRAF tumors with p.V600E-positive non-small-cell lung cancer.


      One patient (6.2%) had a BRAF p.V600E and p.K601_W604 compound mutation with a good clinical response to dabrafenib and trametinib. Molecular dynamics simulation also complemented the effect.


      The combination of a genetic analysis and computational simulation model may help predict the sensitivity for dabrafenib in cases with a rare BRAF compound mutation. The construction of a genomic and simulation fused database is important for the development of personalized medicine in this field.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Cancer Genetics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Frisone D.
        • Friedlaender A.
        • Malapelle U.
        • Banna G.
        • Addeo A.
        A BRAF new world.
        Crit Rev Oncol Hematol. 2020; 152103008
        • Planchard D.
        • Besse B.
        • Groen H.J.M.
        • Souquet P.J.
        • Quoix E.
        • Baik C.S.
        • Barlesi F.
        • Kim T.M.
        • Mazieres J.
        • Novello S.
        • Rigas J.R.
        • Upalawanna A.
        • D'Amelio Jr., A.M.
        • Zhang P.
        • Mookerjee B.
        • Johnson B.E
        Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial.
        Lancet Oncol. 2016; 17: 984-993
        • Planchard D.
        • Smit E.F.
        • Groen H.J.M.
        • Mazieres J.
        • Besse B.
        • Å Helland
        • Giannone V.
        • D'Amelio Jr., A.M.
        • Zhang P.
        • Mookerjee B.
        • Johnson B.E
        Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial.
        Lancet Oncol. 2017; 18: 1307-1316
        • Seto K.
        • Haneda M.
        • Masago K.
        • Fujita S.
        • Kato S.
        • Sasaki E.
        • et al.
        Negative reactions of BRAF mutation-specific immunohistochemistry to non-V600E mutations of BRAF.
        Pathol Int. 2020; 70: 253-261
        • Peng S.B.
        • Henry J.R.
        • Kaufman M.D.
        • Lu W.P.
        • Smith B.D.
        • Vogeti S.
        • et al.
        Inhibition of RAF isoforms and active dimers by LY3009120 leads to anti-tumor activities in RAS or BRAF mutant cancers.
        Cancer Cell. 2015; 28: 384-398
      1. Inc. CCG. Molecular operating environment (MOE). 1010 Sherbrooke St. West, Suite #910, Montreal, QC, H3A 2R7, Canada, 2016.

        • Fujitani H.
        • Tanida Y.
        • Matsuura A.
        Massively parallel computation of absolute binding free energy with well-equilibrated states.
        Phys Rev E, Stat Nonlinear Soft Matter Phys. 2009; 79021914
        • Araki M.
        • Kamiya N.
        • Sato M.
        • Nakatsui M.
        • Hirokawa T.
        • Okuno Y.
        The effect of conformational flexibility on binding free energy estimation between kinases and their inhibitors.
        J Chem Inf Model. 2016; 56: 2445-2456
        • King A.J.
        • Arnone M.R.
        • Bleam M.R.
        • Moss K.G.
        • Yang J.
        • Fedorowicz K.E.
        • et al.
        Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions.
        PLoS ONE. 2013; 8: e67583
        • Malapelle U.
        • Rossi G.
        • Pisapia P.
        • Barberis M.
        • Buttitta F.
        • Castiglione F.
        • et al.
        BRAF as a positive predictive biomarker: focus on lung cancer and melanoma patients.
        Crit Rev Oncol Hematol. 2020; 156103118
        • Tannenbaum J.
        • Rowan A.N.
        Rethinking the morality of animal research.
        Hastings Cent Rep. 1985; 15: 32-43
        • Sneddon L.U.
        • Halsey L.G.
        • Bury N.R.
        Considering aspects of the 3Rs principles within experimental animal biology.
        J Exp Biol. 2017; 220: 3007-3016
        • Morrissey B.
        • Blyth K.
        • Carter P.
        • Chelala C.
        • Jones L.
        • Holen I.
        • et al.
        The sharing experimental animal resources, coordinating holdings (SEARCH) framework: encouraging reduction, replacement, and refinement in animal research.
        PLoS Biol. 2017; 15e2000719
        • Teicher B.A.
        In vivo/ex vivo and in situ assays used in cancer research: a brief review.
        Toxicol Pathol. 2009; 37: 114-122
        • Esch E.W.
        • Bahinski A.
        • Huh D.
        Organs-on-chips at the frontiers of drug discovery.
        Nat Rev Drug Discov. 2015; 14: 248-260
        • Jean-Quartier C.
        • Jeanquartier F.
        • Jurisica I.
        • In Holzinger A.
        silico cancer research towards 3R.
        BMC Cancer. 2018; 18: 408
        • Reyes R.
        • Mayo-de-Las-Casas C.
        • Teixidó C.
        • Cabrera C.
        • Marín E.
        • Vollmer I.
        • et al.
        Clinical benefit from BRAF/MEK inhibition in a double Non-V600E BRAF mutant lung adenocarcinoma: a case report.
        Clin Lung Cancer. 2019; 20: e219-ee23
        • Dagogo-Jack I
        Durable response to dabrafenib combined with trametinib in a patient with NSCLC harboring a BRAF G469A mutation.
        J Thorac Oncol. 2020; 15 (-e6): e174
        • Su P.L.
        • Lin C.Y.
        • Chen Y.L.
        • Chen W.L.
        • Lin C.C.
        • Su W.C.
        Durable response to combined dabrafenib and trametinib in a patient with BRAF K601E mutation-positive lung adenocarcinoma: a case report.
        JTO Clin. Res. Rep. 2021; 2100202