An approach to suppress the evolution of resistance in BRAF(V600E)-mutant cancer Journal Article


Authors: Xue, Y.; Martelotto, L.; Baslan, T.; Vides, A.; Solomon, M.; Mai, T. T.; Chaudhary, N.; Riely, G. J.; Li, B. T.; Scott, K.; Cechhi, F.; Stierner, U.; Chadalavada, K.; de Stanchina, E.; Schwartz, S.; Hembrough, T.; Nanjangud, G.; Berger, M. F.; Nilsson, J.; Lowe, S. W.; Reis-Filho, J. S.; Rosen, N.; Lito, P.
Article Title: An approach to suppress the evolution of resistance in BRAF(V600E)-mutant cancer
Abstract: The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAF amp) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment. The evolutionary selection of BRAF amp was determined by the fitness threshold, the barrier that subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for inhibitors of ERK signaling, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of the RAF, MEK and ERK kinases, however, imposed a sufficiently high fitness threshold to prevent the propagation of subclones with high-level BRAF amp. When administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11 PDXs of lung cancer or melanoma without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and, thus, merit testing in patients. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
Keywords: mitogen activated protein kinase; adult; aged; middle aged; genetics; bevacizumab; cisplatin; raf protein; antineoplastic agent; adenocarcinoma; mouse; animal; animals; mice; in situ hybridization, fluorescence; carboplatin; melanoma; skin neoplasms; protein kinase inhibitor; antineoplastic combined chemotherapy protocols; lung neoplasms; drug resistance; drug screening; pathology; drug resistance, neoplasm; xenograft model antitumor assays; protein kinase inhibitors; fluorescence in situ hybridization; extracellular signal-regulated map kinases; pemetrexed; b raf kinase; mitogen activated protein kinase kinase; mitogen-activated protein kinase kinases; raf kinases; proto-oncogene proteins b-raf; braf protein, human; single cell analysis; single-cell analysis; secondary; drug effects; humans; human; male; female; antagonists and inhibitors
Journal Title: Nature Medicine
Volume: 23
Issue: 8
ISSN: 1078-8956
Publisher: Nature Publishing Group  
Date Published: 2017-08-01
Start Page: 929
End Page: 937
Language: English
DOI: 10.1038/nm.4369
PUBMED: 28714990
PROVIDER: scopus
PMCID: PMC5696266
DOI/URL:
Notes: Article -- Export Date: 2 October 2017 -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    351 Rosen
  2. Piro Lito
    15 Lito
  3. Gregory J Riely
    334 Riely
  4. Michael Forman Berger
    373 Berger
  5. Scott W Lowe
    144 Lowe
  6. Jorge Sergio Reis
    283 Reis
  7. Bob Tingkan Li
    57 Li
  8. Timour Baslan
    15 Baslan
  9. Yaohua Xue
    2 Xue
  10. Alberto Vides
    1 Vides
  11. Thi Trang Mai
    2 Mai