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Cancer Discov DOI:10.1158/2159-8290.CD-17-1227

Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in Colorectal Cancer.

Publication TypeJournal Article
Year of Publication2018
AuthorsHazar-Rethinam, M, Kleyman, M, G Han, C, Liu, D, Ahronian, LG, Shahzade, HA, Chen, L, Parikh, AR, Allen, JN, Clark, JW, Kwak, EL, Faris, JE, Murphy, JE, Hong, TS, Van Seventer, EE, Nadres, B, Hong, CB, Gurski, JM, Jessop, NA, Dias-Santagata, D, A Iafrate, J, Van Allen, EM, Corcoran, RB
JournalCancer Discov
Date Published2018 04
KeywordsAnimals, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Tumor, Colorectal Neoplasms, Drug Resistance, Neoplasm, Female, Humans, MAP Kinase Signaling System, Mice, Mice, Nude, Mutation, Missense, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Whole Exome Sequencing, Xenograft Model Antitumor Assays

Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from patients with colorectal cancer receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a pooled clone system to study clonal outgrowth during acquired resistance, and , the dynamics of individual resistant clones could be monitored in real time in cfDNA isolated from culture media during therapy. Outgrowth of multiple resistant clones was observed during therapy with BRAF, EGFR, and MEK inhibitor combinations. However, ERK inhibition, particularly in combination with BRAF and EGFR inhibition, markedly abrogated clonal outgrowth and Thus, convergent, up-front therapy may suppress outgrowth of heterogeneous clones harboring clinically observed resistance alterations, which may improve clinical outcome. We observed heterogeneous, recurrent alterations in the MAPK pathway as key drivers of acquired resistance in colorectal cancer, with multiple concurrent resistance alterations detectable in individual patients. Using a novel pooled clone system, we identify convergent up-front therapeutic strategies capable of intercepting multiple resistance mechanisms as potential approaches to suppress emergence of acquired resistance. .


Alternate JournalCancer Discov
PubMed ID29431697
PubMed Central IDPMC5882515
Grant ListK08 CA166510 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
R01 CA208437 / CA / NCI NIH HHS / United States
U54 CA224068 / CA / NCI NIH HHS / United States