MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition - PubMed (original) (raw)
Clinical Trial
doi: 10.1158/2159-8290.CD-13-0631. Epub 2013 Nov 21.
Eliezer M Van Allen, Daniel J Treacy, Dennie T Frederick, Zachary A Cooper, Amaro Taylor-Weiner, Mara Rosenberg, Eva M Goetz, Ryan J Sullivan, Deborah N Farlow, Dennis C Friedrich, Kristin Anderka, Danielle Perrin, Cory M Johannessen, Aaron McKenna, Kristian Cibulskis, Gregory Kryukov, Eran Hodis, Donald P Lawrence, Sheila Fisher, Gad Getz, Stacey B Gabriel, Scott L Carter, Keith T Flaherty, Jennifer A Wargo, Levi A Garraway
Affiliations
- PMID: 24265154
- PMCID: PMC3947296
- DOI: 10.1158/2159-8290.CD-13-0631
Clinical Trial
MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition
Nikhil Wagle et al. Cancer Discov. 2014 Jan.
Abstract
Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2(Q60P)). MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal-regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.
Figures
FIGURE 1. Identification of a MEK2 mutation in a melanoma sample resistant to dabrafenib/trametinib
(A) Whole exome sequencing (WES) (left panel) and whole transcriptome sequencing (RNA-Seq) (right panel) of the tumor tissue from Patient 1 both before treatment and after the development of resistance to dabrafenib/trametinib revealed a Q60P mutation in MEK2 in the resistant tumor that was undetectable in the pre-treatment tumor. (B) The fraction of tumor cells (the cancer cell fraction, CCF) harboring each alteration was calculated for the pretreatment and resistant tumor samples. Direct comparison of the CCF for all alterations in the pretreatment and resistant tumor samples demonstrated alterations that occurred in the pretreatment sample only (lower right corner, blue), the resistant sample only (upper left corner, purple), or both samples (upper right corner, red). 15 missense mutations were identified occurring in the resistant sample only (upper left corner, purple), including the MEK2Q60P mutation (see Supplementary Table 3).
FIGURE 2. Pharmacologic and biochemical characterization of the MEK2Q60P mutation
(A-D) Growth inhibition curves are shown for dabrafenib/trametinib (A), as well as monotherapy with dabrafenib (B) or trametinib (C), and the ERK inhibitor VX-11e (D) for A375 (BRAFV600E) melanoma cells (grey) and A375 cells expressing wild type MEK2 (MEK2 WT; blue) or MEK2Q60P (red). (E) The effect of combined dabrafenib/trametinib treatment on ERK1/2 phosphorylation (pERK 1/2) in wild type A375 cells (BRAFV600E) and those expressing wild type MEK2 (MEK2 WT) or MEK2Q60P is shown. The levels of pERK1/2, total ERK1/2, pMEK1/2, total MEK1/2, and vinculin are shown for A375 cells expressing MEK2 mutations after a 16-hour incubation at various drug concentrations as indicated.
FIGURE 3. Additional secondary alterations in MAP kinase pathway identified in resistant tumors
(A) RNA-Seq of the tumor tissue from Patient 2 both before treatment and after the development of resistance to dabrafenib/trametinib revealed a BRAF splice isoform lacking exons 2-10 in the resistant tumor that was undetectable in the pre-treatment tumor. (B). Copy number analysis of whole exome data from Patient 3 demonstrates 2 highly amplified regions in the resistant tumor that are not amplified in the pre-treatment tumor. One of these regions contains the BRAF gene, while the second region contains multiple genes, including SAMD4B.
Comment in
- Therapeutics: delving deeper into resistance.
Seton-Rogers S. Seton-Rogers S. Nat Rev Cancer. 2014 Jan;14(1):7. doi: 10.1038/nrc3653. Nat Rev Cancer. 2014. PMID: 24505615 No abstract available.
Similar articles
- Clinical, Molecular, and Immune Analysis of Dabrafenib-Trametinib Combination Treatment for BRAF Inhibitor-Refractory Metastatic Melanoma: A Phase 2 Clinical Trial.
Chen G, McQuade JL, Panka DJ, Hudgens CW, Amin-Mansour A, Mu XJ, Bahl S, Jané-Valbuena J, Wani KM, Reuben A, Creasy CA, Jiang H, Cooper ZA, Roszik J, Bassett RL Jr, Joon AY, Simpson LM, Mouton RD, Glitza IC, Patel SP, Hwu WJ, Amaria RN, Diab A, Hwu P, Lazar AJ, Wargo JA, Garraway LA, Tetzlaff MT, Sullivan RJ, Kim KB, Davies MA. Chen G, et al. JAMA Oncol. 2016 Aug 1;2(8):1056-64. doi: 10.1001/jamaoncol.2016.0509. JAMA Oncol. 2016. PMID: 27124486 Free PMC article. Clinical Trial. - Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.
Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Flaherty KT, et al. N Engl J Med. 2012 Nov 1;367(18):1694-703. doi: 10.1056/NEJMoa1210093. Epub 2012 Sep 29. N Engl J Med. 2012. PMID: 23020132 Free PMC article. Clinical Trial. - [Treatment of BRAF-mutated metastatic melanoma].
Boyles TB, Svane IM, Bastholt L, Schmidt H. Boyles TB, et al. Ugeskr Laeger. 2016 Aug 29;178(35):V02160126. Ugeskr Laeger. 2016. PMID: 27592869 Review. Danish. - Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial.
Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A, Stroyakovskiy D, Drucis K, Grange F, Chiarion-Sileni V, Rutkowski P, Lichinitser M, Levchenko E, Wolter P, Hauschild A, Long GV, Nathan P, Ribas A, Flaherty K, Sun P, Legos JJ, McDowell DO, Mookerjee B, Schadendorf D, Robert C. Grob JJ, et al. Lancet Oncol. 2015 Oct;16(13):1389-98. doi: 10.1016/S1470-2045(15)00087-X. Lancet Oncol. 2015. PMID: 26433819 Clinical Trial. - Combined BRAF and MEK inhibition for the treatment of BRAF-mutated metastatic melanoma.
Queirolo P, Picasso V, Spagnolo F. Queirolo P, et al. Cancer Treat Rev. 2015 Jun;41(6):519-26. doi: 10.1016/j.ctrv.2015.04.010. Epub 2015 Apr 29. Cancer Treat Rev. 2015. PMID: 25944484 Review.
Cited by
- Targeting the p90RSK/MDM2/p53 Pathway Is Effective in Blocking Tumors with Oncogenic Up-Regulation of the MAPK Pathway Such as Melanoma and Lung Cancer.
Maietta I, Viscusi E, Laudati S, Iannaci G, D'Antonio A, Melillo RM, Motti ML, De Falco V. Maietta I, et al. Cells. 2024 Sep 14;13(18):1546. doi: 10.3390/cells13181546. Cells. 2024. PMID: 39329730 Free PMC article. - Therapeutic advances of targeting receptor tyrosine kinases in cancer.
Tomuleasa C, Tigu AB, Munteanu R, Moldovan CS, Kegyes D, Onaciu A, Gulei D, Ghiaur G, Einsele H, Croce CM. Tomuleasa C, et al. Signal Transduct Target Ther. 2024 Aug 14;9(1):201. doi: 10.1038/s41392-024-01899-w. Signal Transduct Target Ther. 2024. PMID: 39138146 Free PMC article. Review. - Current State of Targeted Therapy in Adult Langerhans Cell Histiocytosis and Erdheim-Chester Disease.
Lin H, Cao XX. Lin H, et al. Target Oncol. 2024 Sep;19(5):691-703. doi: 10.1007/s11523-024-01080-x. Epub 2024 Jul 11. Target Oncol. 2024. PMID: 38990463 Review. - Extracellular vesicles promote migration despite BRAF inhibitor treatment in malignant melanoma cells.
Németh A, Bányai GL, Dobos NK, Kós T, Gaál A, Varga Z, Buzás EI, Khamari D, Dank M, Takács I, Szász AM, Garay T. Németh A, et al. Cell Commun Signal. 2024 May 22;22(1):282. doi: 10.1186/s12964-024-01660-4. Cell Commun Signal. 2024. PMID: 38778340 Free PMC article. - From standard therapies to monoclonal antibodies and immune checkpoint inhibitors - an update for reconstructive surgeons on common oncological cases.
Knoedler L, Huelsboemer L, Hollmann K, Alfertshofer M, Herfeld K, Hosseini H, Boroumand S, Stoegner VA, Safi AF, Perl M, Knoedler S, Pomahac B, Kauke-Navarro M. Knoedler L, et al. Front Immunol. 2024 Apr 23;15:1276306. doi: 10.3389/fimmu.2024.1276306. eCollection 2024. Front Immunol. 2024. PMID: 38715609 Free PMC article. Review.
References
- Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. The New England journal of medicine. 2012 Jul 12;367(2):107–14. PubMed PMID: 22663011. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- P30 CA016672/CA/NCI NIH HHS/United States
- U54 HG003067/HG/NHGRI NIH HHS/United States
- P01 CA163222 01A1/CA/NCI NIH HHS/United States
- T32 GM007753/GM/NIGMS NIH HHS/United States
- T32 CA009172/CA/NCI NIH HHS/United States
- DP2 OD002750/OD/NIH HHS/United States
- 5U54HG003067-11/HG/NHGRI NIH HHS/United States
- P01 CA163222/CA/NCI NIH HHS/United States
- P50 CA093683/CA/NCI NIH HHS/United States
- P50CA93683/CA/NCI NIH HHS/United States
- R33 CA155554/CA/NCI NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous