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Posts Tagged ‘rTKs’


Resistance to Receptor of Tyrosine Kinase

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Two just published articles in Science Translational Medicine report

(1) the discovery of bypass mechanisms of resistance to the receptor of tyrosine kinase inhibition (rTKI) in lung cancer
(2) receptor signaling networks in predicting drug response

Bypass Mechanisms of Resistance to Receptor Tyrosine Kinase Inhibition in Lung Cancer

Matthew J. Niederst1,2 and Jeffrey A. Engelman1,2*
1 Massachusetts General Hospital Cancer Center, Charlestown, MA
2 Department of Medicine, Harvard Medical School, Boston, MA
Sci. Signal., 24 Sep 2013; 6(294), p. re6
http://dx.doi.org/10.1126/scisignal.2004652

Abstract: Receptor tyrosine kinases (RTKs) are activated by somatic genetic alterations in a subset of cancers, and

  • such cancers are often sensitive to specific inhibitors of the activated kinase.

Two well-established examples of this paradigm include

  • lung cancers with either EGFR mutations or
  • ALK translocations.

In these cancers, inhibition of the corresponding RTK

  • leads to suppression of key downstream signaling pathways, such as
    • the PI3K (phosphatidylinositol 3-kinase)/AKT and
    • MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal–regulated kinase) pathways,

resulting in cell growth arrest and death.

Despite the initial clinical efficacy of ALK (anaplastic lymphoma kinase) and EGFR (epidermal growth factor receptor) inhibitors in these cancers,

  • resistance invariably develops, typically within 1 to 2 years.

Over the past several years, multiple molecular mechanisms of resistance have been identified, and some common themes have emerged. These are

  1. the development of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective RTK.
  2. activation of alternative RTKs that maintain the signaling of key downstream pathways
    • despite sustained inhibition of the original drug target.

Indeed, several different RTKs have been implicated in promoting resistance to EGFR and ALK inhibitors in both laboratory studies and patient samples.

In this mini-review, we summarize

  1. the concepts underlying RTK-mediated resistance,
  2. the specific examples known to date, and
  3. the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.

* Corresponding author. E-mail: jengelman@partners.org

Citation: M. J. Niederst, J. A. Engelman, Bypass Mechanisms of Resistance to Receptor Tyrosine Kinase Inhibition in Lung Cancer. Sci. Signal. 6, re6 (2013).

Profiles of Basal and Stimulated Receptor Signaling Networks Predict Drug Response in Breast Cancer Lines

Mario Niepel1*{dagger}, Marc Hafner1{dagger}, Emily A. Pace2{dagger}, Mirra Chung1, Diana H. Chai2, Lili Zhou1, Birgit Schoeberl2, and Peter K. Sorger1*
1 Harvard Medical School Library of Integrated Network-based Cellular Signatures Center, Department of Systems Biology, Harvard Medical School, Boston, MA
2 Merrimack Pharmaceuticals, Cambridge, MA
Sci. Signal., 24 Sep 2013; 6(294), p. ra84
Abstract: Identifying factors responsible for variation in drug response is essential for the effective use of targeted therapeutics. We profiled signaling pathway activity in a collection of breast cancer cell lines
  • before and after stimulation with physiologically relevant ligands, which
  • revealed the variability in network activity among cells of known genotype and molecular subtype.
Despite the receptor-based classification of breast cancer subtypes, we found that
  • the abundance and activity of signaling proteins in unstimulated cells (basal profile), as well as
  • the activity of proteins in stimulated cells (signaling profile),
varied within each subtype.
Using a partial least-squares regression approach, we constructed models that significantly predicted sensitivity to 23 targeted therapeutics. For example,
  • one model showed that the response to the growth factor receptor ligand heregulin effectively predicted
    • the sensitivity of cells to drugs targeting the cell survival pathway mediated by PI3K (phosphoinositide 3-kinase) and Akt, whereas
    • the abundance of Akt or the mutational status of the enzymes in the pathway did not.
Thus, basal and signaling protein profiles may yield new biomarkers of drug sensitivity and enable the identification of appropriate therapies in cancers characterized by similar functional dysregulation of signaling networks.
* Corresponding author. E-mail: peter_sorger@hms.harvard.edu (P.K.S.); mario_niepel@hms.harvard.edu (M.N.)
Citation: M. Niepel, M. Hafner, E. A. Pace, M. Chung, D. H. Chai, L. Zhou, B. Schoeberl, P. K. Sorger, Profiles of Basal and Stimulated Receptor Signaling Networks Predict Drug Response in Breast Cancer Lines. Sci. Signal. 6, ra84 (2013).
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