Cancer Discovery
Cancer Discovery
5 years ago

Convergent therapeutic strategies to overcome the heterogeneity of acquired resistance in BRAFV600E colorectal cancer.

Heather A Shahzade, Catriona B Hong, David Liu, Jason E Faris, Brandon Nadres, Joseph M Gurski, Theodore S Hong, Eliezer M Van Allen, A John Iafrate, Janet E Murphy, Jeffrey W Clark, Jill N Allen, Nicholas A Jessop, Marianna Kleyman, Eunice L Kwak, Lifeng Chen, Leanne G Ahronian, Ryan B Corcoran, Emily E Van Seventer, Aparna R Parikh, Mehlika Hazar-Rethinam, Dora Dias-Santagata, G Celine Han
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 BRAFV600E colorectal cancer patients 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 novel pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivo. In vitro, 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 in vitro and in vivo. Thus, convergent, upfront therapy may suppress outgrowth of heterogeneous clones harboring clinically observed resistance alterations, which may improve clinical outcome.

Publisher URL: http://doi.org/10.1158/2159-8290.CD-17-1227

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

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.