Metrics other than potency reveal systematic variation in responses to cancer drugs

Mohammad Fallahi-Sichani, Saman Honarnejad, Laura Heiser, Joe Gray, Peter K. Sorger

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

Large-scale analysis of cellular response to anticancer drugs typically focuses on variation in potency (half-maximum inhibitory concentration, (IC 50)), assuming that it is the most important difference between effective and ineffective drugs or sensitive and resistant cells. We took a multiparametric approach involving analysis of the slope of the dose-response curve, the area under the curve and the maximum effect (E max). We found that some of these parameters vary systematically with cell line and others with drug class. For cell-cycle inhibitors, E max often but not always correlated with cell proliferation rate. For drugs targeting the Akt/PI3K/mTOR pathway, dose-response curves were unusually shallow. Classical pharmacology has no ready explanation for this phenomenon, but single-cell analysis showed that it correlated with significant and heritable cell-to-cell variability in the extent of target inhibition. We conclude that parameters other than potency should be considered in the comparative analysis of drug response, particularly at clinically relevant concentrations near and above the IC 50.

Original languageEnglish (US)
Pages (from-to)708-714
Number of pages7
JournalNature Chemical Biology
Volume9
Issue number11
DOIs
StatePublished - Nov 2013

Fingerprint

Pharmaceutical Preparations
Neoplasms
Single-Cell Analysis
Drug Delivery Systems
Phosphatidylinositol 3-Kinases
Inhibitory Concentration 50
Area Under Curve
Cell Cycle
Cell Proliferation
Pharmacology
Cell Line

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Metrics other than potency reveal systematic variation in responses to cancer drugs. / Fallahi-Sichani, Mohammad; Honarnejad, Saman; Heiser, Laura; Gray, Joe; Sorger, Peter K.

In: Nature Chemical Biology, Vol. 9, No. 11, 11.2013, p. 708-714.

Research output: Contribution to journalArticle

Fallahi-Sichani, Mohammad ; Honarnejad, Saman ; Heiser, Laura ; Gray, Joe ; Sorger, Peter K. / Metrics other than potency reveal systematic variation in responses to cancer drugs. In: Nature Chemical Biology. 2013 ; Vol. 9, No. 11. pp. 708-714.
@article{5d3829658fbb47cd9bd3ed1030eab0a7,
title = "Metrics other than potency reveal systematic variation in responses to cancer drugs",
abstract = "Large-scale analysis of cellular response to anticancer drugs typically focuses on variation in potency (half-maximum inhibitory concentration, (IC 50)), assuming that it is the most important difference between effective and ineffective drugs or sensitive and resistant cells. We took a multiparametric approach involving analysis of the slope of the dose-response curve, the area under the curve and the maximum effect (E max). We found that some of these parameters vary systematically with cell line and others with drug class. For cell-cycle inhibitors, E max often but not always correlated with cell proliferation rate. For drugs targeting the Akt/PI3K/mTOR pathway, dose-response curves were unusually shallow. Classical pharmacology has no ready explanation for this phenomenon, but single-cell analysis showed that it correlated with significant and heritable cell-to-cell variability in the extent of target inhibition. We conclude that parameters other than potency should be considered in the comparative analysis of drug response, particularly at clinically relevant concentrations near and above the IC 50.",
author = "Mohammad Fallahi-Sichani and Saman Honarnejad and Laura Heiser and Joe Gray and Sorger, {Peter K.}",
year = "2013",
month = "11",
doi = "10.1038/nchembio.1337",
language = "English (US)",
volume = "9",
pages = "708--714",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - Metrics other than potency reveal systematic variation in responses to cancer drugs

AU - Fallahi-Sichani, Mohammad

AU - Honarnejad, Saman

AU - Heiser, Laura

AU - Gray, Joe

AU - Sorger, Peter K.

PY - 2013/11

Y1 - 2013/11

N2 - Large-scale analysis of cellular response to anticancer drugs typically focuses on variation in potency (half-maximum inhibitory concentration, (IC 50)), assuming that it is the most important difference between effective and ineffective drugs or sensitive and resistant cells. We took a multiparametric approach involving analysis of the slope of the dose-response curve, the area under the curve and the maximum effect (E max). We found that some of these parameters vary systematically with cell line and others with drug class. For cell-cycle inhibitors, E max often but not always correlated with cell proliferation rate. For drugs targeting the Akt/PI3K/mTOR pathway, dose-response curves were unusually shallow. Classical pharmacology has no ready explanation for this phenomenon, but single-cell analysis showed that it correlated with significant and heritable cell-to-cell variability in the extent of target inhibition. We conclude that parameters other than potency should be considered in the comparative analysis of drug response, particularly at clinically relevant concentrations near and above the IC 50.

AB - Large-scale analysis of cellular response to anticancer drugs typically focuses on variation in potency (half-maximum inhibitory concentration, (IC 50)), assuming that it is the most important difference between effective and ineffective drugs or sensitive and resistant cells. We took a multiparametric approach involving analysis of the slope of the dose-response curve, the area under the curve and the maximum effect (E max). We found that some of these parameters vary systematically with cell line and others with drug class. For cell-cycle inhibitors, E max often but not always correlated with cell proliferation rate. For drugs targeting the Akt/PI3K/mTOR pathway, dose-response curves were unusually shallow. Classical pharmacology has no ready explanation for this phenomenon, but single-cell analysis showed that it correlated with significant and heritable cell-to-cell variability in the extent of target inhibition. We conclude that parameters other than potency should be considered in the comparative analysis of drug response, particularly at clinically relevant concentrations near and above the IC 50.

UR - http://www.scopus.com/inward/record.url?scp=84886509950&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886509950&partnerID=8YFLogxK

U2 - 10.1038/nchembio.1337

DO - 10.1038/nchembio.1337

M3 - Article

VL - 9

SP - 708

EP - 714

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 11

ER -