Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Pairwise tests for conditional selection use evolutionary logic to predict intrinsic drug resistance in ALK alterations

View ORCID ProfileHaider Inam, Justin Pritchard
doi: https://doi.org/10.1101/696294
Haider Inam
The Pennsylvania State University, Department of Biomedical Engineering, University Park PA, 16802
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Haider Inam
Justin Pritchard
The Pennsylvania State University, Department of Biomedical Engineering, University Park PA, 16802The Huck Institute for the Life Sciences, Center for the Resistance Evolution, The Pennsylvania State University
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: Jrp94@psu.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Data/Code
  • Preview PDF
Loading

Abstract

Background Genomic data can facilitate personalized treatment decisions by enabling therapeutic hypotheses in individual patients. Conditional selection (encompassing both mutual exclusivity and co-occurrence) is commonly used to consider rare genomic variants relative to established cancer drivers. However, the direct comparison of p-values across multiple pairs of genes is confounded by the often-dramatic differences in sample size between established driver mutations and novel findings.

Methods We develop a resampling based method for the direct pairwise comparisons of conditional selection between sets of gene pairs. This effectively creates quantitative positive control guideposts of conditional selection that normalize differences in population size. We applied this method to a transcript variant of ALK in melanoma, termed ALKATI, which has been the subject of a recent controversy in the literature. We reproduced some of the original cell transformation experiments, performed rescue experiments, and analyzed drug response data to revisit the original ALKATI findings.

Finding We found that we are powered to quantitatively compare the degree of relative mutual exclusivity (down to an abundance of 10 patients in a cohort of 500) between novel gene variants and positive controls. We also found that ALKATI is not as mutually exclusive as BRAF and NRAS are with each other. Our in vitro transformation assays and rescue assays suggested that alternative transcript initiation in ALK is not likely to be necessary or sufficient for cellular transformation or growth.

Interpretation Pairwise comparisons of conditional selection represent a sensitive method of utilizing existing genomic data to directly and quantitatively compare relative levels of conditional selection. The results of using our method in ALKATI and our experiments strongly disfavor the role of ALKATI as a targetable oncogenic driver. The progress of other experimental agents in late stage melanoma and our experimental and computational re-analysis led us to conclude that further single agent testing of ALK inhibitors in patients with ALKATI should be limited to cases where no other treatment hypotheses can be identified.

Footnotes

  • https://pritchardlabatpsu.github.io/pairwisecomparisons/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Back to top
PreviousNext
Posted July 09, 2019.
Download PDF
Data/Code
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Pairwise tests for conditional selection use evolutionary logic to predict intrinsic drug resistance in ALK alterations
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
Share
Pairwise tests for conditional selection use evolutionary logic to predict intrinsic drug resistance in ALK alterations
Haider Inam, Justin Pritchard
bioRxiv 696294; doi: https://doi.org/10.1101/696294
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Pairwise tests for conditional selection use evolutionary logic to predict intrinsic drug resistance in ALK alterations
Haider Inam, Justin Pritchard
bioRxiv 696294; doi: https://doi.org/10.1101/696294

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Bioengineering
Subject Areas
All Articles
  • Animal Behavior and Cognition (1519)
  • Biochemistry (2470)
  • Bioengineering (1725)
  • Bioinformatics (9644)
  • Biophysics (3875)
  • Cancer Biology (2957)
  • Cell Biology (4170)
  • Clinical Trials (135)
  • Developmental Biology (2619)
  • Ecology (4083)
  • Epidemiology (2031)
  • Evolutionary Biology (6865)
  • Genetics (5195)
  • Genomics (6479)
  • Immunology (2176)
  • Microbiology (6905)
  • Molecular Biology (2742)
  • Neuroscience (17195)
  • Paleontology (125)
  • Pathology (425)
  • Pharmacology and Toxicology (703)
  • Physiology (1050)
  • Plant Biology (2477)
  • Scientific Communication and Education (642)
  • Synthetic Biology (826)
  • Systems Biology (2678)
  • Zoology (428)