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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).

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