Search: onr:"swepub:oai:gup.ub.gu.se/257189" >
An approach to supp...
An approach to suppress the evolution of resistance in BRAF(V600E)-mutant cancer
-
Xue, Y. H. (author)
-
Martelotto, L. (author)
-
Baslan, T. (author)
-
show more...
-
Vides, A. (author)
-
Solomon, M. (author)
-
Mai, T. T. (author)
-
Chaudhary, N. (author)
-
Riely, G. J. (author)
-
Li, B. T. (author)
-
Scott, K. (author)
-
Cechhi, F. (author)
-
- Stierner, Ulrika, 1952 (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center
-
Chadalavada, K. (author)
-
de Stanchina, E. (author)
-
Schwartz, S. (author)
-
Hembrough, T. (author)
-
Nanjangud, G. (author)
-
- Nilsson, Jonas A, 1971 (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center
-
Lowe, S. W. (author)
-
Reis, J. (author)
-
Rosen, N. (author)
-
Lito, P. (author)
-
show less...
-
(creator_code:org_t)
- 2017-07-17
- 2017
- English.
-
In: Nat Med. - : Springer Science and Business Media LLC. - 1078-8956. ; 23:8
- Related links:
-
https://europepmc.or...
-
show more...
-
https://gup.ub.gu.se...
-
https://doi.org/10.1...
-
show less...
Abstract
Subject headings
Close
- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- cell lung-cancer
- braf-mutant
- mek inhibition
- raf inhibitors
- phase-2
- trial
- open-label
- melanoma
- feedback
- multicenter
- vemurafenib
- Biochemistry & Molecular Biology
- Cell Biology
- Research & Experimental
- Medicine
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
-
Nat Med
(Search for host publication in LIBRIS)
To the university's database
- By the author/editor
-
Xue, Y. H.
-
Martelotto, L.
-
Baslan, T.
-
Vides, A.
-
Solomon, M.
-
Mai, T. T.
-
show more...
-
Chaudhary, N.
-
Riely, G. J.
-
Li, B. T.
-
Scott, K.
-
Cechhi, F.
-
Stierner, Ulrika ...
-
Chadalavada, K.
-
de Stanchina, E.
-
Schwartz, S.
-
Hembrough, T.
-
Nanjangud, G.
-
Nilsson, Jonas A ...
-
Lowe, S. W.
-
Reis, J.
-
Rosen, N.
-
Lito, P.
-
show less...
- About the subject
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Clinical Medicin ...
-
and Cancer and Oncol ...
- Articles in the publication
-
Nat Med
-
Nature Medicine
- By the university
-
University of Gothenburg