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Activity and Resistance of a Brain-Permeable Paradox Breaker BRAF Inhibitor in Melanoma Brain Metastasis

Overview of attention for article published in Cancer Research, June 2022
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  • In the top 5% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (95th percentile)
  • High Attention Score compared to outputs of the same age and source (96th percentile)

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5 news outlets
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23 tweeters
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Title
Activity and Resistance of a Brain-Permeable Paradox Breaker BRAF Inhibitor in Melanoma Brain Metastasis
Published in
Cancer Research, June 2022
DOI 10.1158/0008-5472.can-21-4152
Pubmed ID
Authors

Ester Bonfill-Teixidor, Raffaella Iurlaro, Cornelia Handl, Jürgen Wichmann, Alexandra Arias, Isabel Cuartas, Jasmin Emmenegger, Andrea Romagnani, Luca Mangano, Thomas Lorber, Marco Berrera, Christina Godfried Sie, Fabian Köchl, Jan Eckmann, Romi Feddersen, Martin Kornacker, Gabriel Schnetzler, Marta Cicuendez, Esteban Cordero, Thomaz E. Topczewski, Abel Ferres-Pijoan, Josep González, Francisco Martínez-Ricarte, Eva Muñoz-Couselo, Josep Tabernero, James R. Bischoff, Piergiorgio Pettazzoni, Joan Seoane

Abstract

The therapeutic benefit of approved BRAF and MEK inhibitors (BRAFi/MEKi) in patients with brain metastatic BRAF V600E/K-mutated melanoma is limited and transient. Resistance largely occurs through the restoration of MAPK signaling via paradoxical BRAF activation, highlighting the need for more effective therapeutic options. Aiming to address this clinical challenge, we characterized the activity of a potent, brain-penetrant paradox breaker BRAFi (compound 1a, C1a) as first line therapy and following progression upon treatment with approved BRAFi and BRAFi/MEKi therapies. C1a activity was evaluated in vitro and in vivo in melanoma cell lines and patient-derived models of BRAF V600E-mutant melanoma brain metastases following relapse after treatment with BRAFi/MEKi. C1a showed superior efficacy compared to approved BRAFi, both in subcutaneous and brain metastatic models. Importantly, C1a manifested potent and prolonged antitumor activity even in models that progressed on BRAFi/MEKi treatment. Analysis of mechanisms of resistance to C1a revealed MAPK reactivation under drug treatment as the predominant resistance-driving event in both subcutaneous and intracranial tumors. Specifically, BRAF kinase domain duplication was identified as a frequently occurring driver of resistance to C1a. Combination therapies of C1a and anti-PD1 antibody proved to significantly reduce disease recurrence. Collectively, these preclinical studies validate the outstanding antitumor activity of C1a in brain metastasis, support clinical investigation of this agent in patients pretreated with BRAFi/MEKi, unveil genetic drivers of tumor escape from C1a, and identify a combinatorial treatment that achieves long-lasting responses.

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Attention Score in Context

This research output has an Altmetric Attention Score of 52. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 27 June 2022.
All research outputs
#631,280
of 21,479,159 outputs
Outputs from Cancer Research
#428
of 17,413 outputs
Outputs of similar age
#12,886
of 304,746 outputs
Outputs of similar age from Cancer Research
#6
of 132 outputs
Altmetric has tracked 21,479,159 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 97th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 17,413 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.4. This one has done particularly well, scoring higher than 97% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 304,746 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 95% of its contemporaries.
We're also able to compare this research output to 132 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 96% of its contemporaries.