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Tunable-Combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Cotargeting but Result in Melanoma Drug Addiction
Open accessAbstract
SUMMARY Combined BRAF and MEK targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. V600EBRAF, expressed at supra-physiological levels because of V600EBRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with over-expressed V600EBRAF via a regulatory interface at R662 of V600EBRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity.
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A landscape of driver mutations in melanoma
Hodis, E., Watson, I. R., Kryukov, G. V., Arold, S. T., Imielinski, M., Theurillat, J.-P., Nickerson, E., Auclair, D., Li, L., Place, C., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.024 · Cited by 2,610
RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)
Poulikakos, P. I., Persaud, Y., Janakiraman, M., Kong, X., Ng, C., Moriceau, G., Shi, H., Atefi, M., Titz, B., Gabay, M. T., et al. (2011) · Nature · doi:10.1038/nature10662 · Cited by 1,454
Self-citationModelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance
Das Thakur, M., Salangsang, F., Landman, A. S., Sellers, W. R., Pryer, N. K., Levesque, M. P., Dummer, R., McMahon, M., & Stuart, D. D. (2013) · Nature · doi:10.1038/nature11814 · Cited by 730
Wagle, N., Van Allen, E. M., Treacy, D. J., Frederick, D. T., Cooper, Z. A., Taylor-Weiner, A., Rosenberg, M., Goetz, E. M., Sullivan, R. J., Farlow, D. N., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0631 · Cited by 478
Cited by
Drug resistance and combating drug resistance in cancer
Wang, X., Zhang, H., & Chen, X. (2019) · Cancer Drug Resistance · doi:10.20517/cdr.2019.10 · Cited by 1,085
Regulated cell death (RCD) in cancer: key pathways and targeted therapies
Peng, F., Liao, M., Qin, R., Zhu, S., Peng, C., Fu, L., Chen, Y., & Han, B. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01110-y · Cited by 832
MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road
Caunt, C. J., Sale, M. J., Smith, P. D., & Cook, S. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc4000 · Cited by 606
Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance
Hugo, W., Shi, H., Sun, L., Piva, M., Song, C., Kong, X., Moriceau, G., Hong, A., Dahlman, K. B., Johnson, D. B., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.061 · Cited by 600
Self-citationMutant BRAF and MEK inhibitors regulate the tumor immune microenvironment via pyroptosis
Erkes, D. A., Cai, W., Sanchez, I. M., Purwin, T. J., Rogers, C., Field, C. O., Berger, A. C., Hartsough, E. J., Rodeck, U., Alnemri, E. S., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0672 · Cited by 459
Metadata
- Authors
- Moriceau, G., Hugo, W., Hong, A., Shi, H., Kong, X., Yu, C. C., Koya, R. C., Samatar, A. A., Khanlou, N., Braun, J., Ruchalski, K., Seifert, H., Larkin, J., Dahlman, K. B., Johnson, D. B., Algazi, A., Sosman, J. A., Ribas, A., & Lo, R. S.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 27
- Issue
- 2
- Pages
- 240-256
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2040286515
- Cited by
- 345
- References
- 4
- FWCI
- 15.44
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Moriceau, G., Hugo, W., Hong, A., Shi, H., Kong, X., Yu, C. C., Koya, R. C., Samatar, A. A., Khanlou, N., Braun, J., Ruchalski, K., Seifert, H., Larkin, J., Dahlman, K. B., Johnson, D. B., Algazi, A., Sosman, J. A., Ribas, A., & Lo, R. S. (2015). Tunable-Combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Cotargeting but Result in Melanoma Drug Addiction. Cancer Cell. https://doi.org/10.1016/j.ccell.2014.11.018
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
