Title | An approach to suppress the evolution of resistance in BRAF-mutant cancer. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Xue Y, Martelotto L, Baslan T, Vides A, Solomon M, Mai TThi, Chaudhary N, Riely GJ, Li BT, Scott K, Cechhi F, Stierner U, Chadalavada K, de Stanchina E, Schwartz S, Hembrough T, Nanjangud G, Berger MF, Nilsson J, Lowe SW, Reis-Filho JS, Rosen N, Lito P |
Journal | Nat Med |
Volume | 23 |
Issue | 8 |
Pagination | 929-937 |
Date Published | 2017 Aug |
ISSN | 1546-170X |
Keywords | Adenocarcinoma, Adenocarcinoma of Lung, Adult, Aged, Animals, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Carboplatin, Cisplatin, Drug Resistance, Neoplasm, Extracellular Signal-Regulated MAP Kinases, Female, Humans, In Situ Hybridization, Fluorescence, Lung Neoplasms, Male, Melanoma, Mice, Middle Aged, Mitogen-Activated Protein Kinase Kinases, Pemetrexed, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, raf Kinases, Single-Cell Analysis, Skin Neoplasms, Xenograft Model Antitumor Assays |
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) 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 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. 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. |
DOI | 10.1038/nm.4369 |
Alternate Journal | Nat. Med. |
PubMed ID | 28714990 |
PubMed Central ID | PMC5696266 |
Grant List | U54 OD020355 / OD / NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States R35 CA210085 / CA / NCI NIH HHS / United States K08 CA191082 / CA / NCI NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States P01 CA129243 / CA / NCI NIH HHS / United States |
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