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Epidermal growth factor receptor mutations in lung cancer

Key Points

  • Advanced non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the world.

  • Epidermal growth factor receptor (EGFR) is expressed in 50% of NSCLCs, and its expression is correlated with poor prognosis. These two factors make EGFR and its family members prime candidates for the development of targeted therapeutics.

  • Two EGFR-targeting small-molecule inhibitors, gefitinib (Iressa: AstraZeneca, approved in May 2003) and erlotinib (Tarceva: OSI-Genentech, approved in November 2004) received fast-track approval from the US Food and Drug Administration as treatment for patients with advanced NSCLC who had failed to respond to conventional chemotherapy.

  • Early clinical data showed that 10% of patients with NSCLC responded to gefitinib or erlotinib. Although infrequent, the speed and magnitude of clinical responses were unique, as was the fact that they were seen in specific subsets of cases (non-smokers, women, East Asians and patients with adenocarcinomas with bronchioloalveolar histology).

  • Molecular analysis showed that in most instances, responders harboured specific mutations in the gene that encodes EGFR. Exon 19 mutations characterized by in-frame deletions of amino-acids 747–750 account for 45% of mutations, exon 21 mutations resulting in L858R substitutions account for 40–45% of mutations, and the remaining 10% of mutations involve exon 18 and 20.

  • EGFR kinase domain mutations hyperactivate the kinase and confer a dependence on the mutated kinase for the survival of the NSCLC tumour cells.

  • The treatment of sensitive cells with targeted therapeutics such as gefitinib and erlotinib seems to trigger a form of 'oncogenic shock', which is postulated to result from the differential decay of downstream signals leading to a temporary predominance of apoptotic signals.

  • Acquired resistance to gefitinib and erlotinib might involve the recurrent mutation T790M which affects the gatekeeper residue in the catalytic domain of the kinase that weakens the interaction of the inhibitor with its target. Resistance can be overcome in vitro by irreversible inhibitors of EGFR

Abstract

The development and clinical application of inhibitors that target the epidermal growth factor receptor (EGFR) provide important insights for new lung cancer therapies, as well as for the broader field of targeted cancer therapies. We review the results of genetic, biochemical and clinical studies focused on somatic mutations of EGFR that are associated with the phenomenon of oncogene addiction, describing 'oncogenic shock' as a mechanistic explanation for the apoptosis that follows the acute treatment of susceptible cells with kinase inhibitors. Understanding the genetic heterogeneity of epithelial tumours and devising strategies to circumvent their rapid acquisition of resistance to targeted kinase inhibitors are essential to the successful use of targeted therapies in common epithelial cancers.

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Figure 1: Gefitinib- and erlotinib-sensitizing mutations of EGFR in NSCLC.
Figure 2: Why gefitinib failed in the United States.
Figure 3: NSCLC cell lines: in vitro surrogates of in vivo drug sensitivity.
Figure 4: The role of differential signal attenuation in inducing oncogenic shock.
Figure 5: Cell-survival pathways downstream of activated erbB receptor tyrosine kinases.

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Acknowledgements

The authors would like to thank T.-M. Chin and L. Sequist Van Dam for their helpful comments. We apologize to our many colleagues whose work is not cited owing to space constraints. Another notable omission is the very important area of antibody-based ErbB-targeted therapies, which is dealt with very well in other reviews.

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Glossary

Neural crest

A pluripotent, ectodermally derived ridge-like cluster of cells found on either side of the neural tube in vertebrate embryos.

Cytotoxic chemotherapy

Chemicals or drugs that kill proliferating cells, especially cancer cells. Their side effects are typically related to the inhibition of normal cell proliferation, with a narrow window of selectivity for cancer cells.

Molecular-targeted therapeutics

Chemicals or drugs that target known proteins that are important in cancer cell proliferation or survival at the same time as being dispensable to normal cells. Although side effects are typically less severe than with cytotoxic agents, the effective inhibition of the target protein might not translate into generally effective therapies, hence the importance of reliable biomarkers.

Autocrine loop

A mode of cell signalling in which soluble ligands released by cells stimulate receptors on their own cell surfaces.

Reversible inhibitors

Inhibitors that bind non-covalently with biological molecules and interfere with their activity.

Unselected patients

A cohort of patients identified on the basis of tissue diagnosis but not correlated with biomarkers (that is, sequencing of the EGFR gene was not used as a selection criterion).

Ligand independence

The activation of a receptor in the absence of interaction with its cognate ligand.

Kcat

The overall catalytic rate of an enzyme (that is, the number of substrate molecules converted to product by each catalytic site per unit of time.

Km

The Michaelis–Menten constant. Km is a measure of the affinity of a substrate for an enzyme, and is the substrate concentration at half the maximal velocity of an enzyme.

Ki

The dissociation constant for the binding of an inhibitor to an enzyme.

Phage-display method

A method in which proteins or peptides are displayed on the surface of filamentous bacteriophages, which can then be used to study the interaction of the peptide with other proteins or chemicals.

Oncogenic shock

A mechanism to explain oncogene addiction, in which the acute inactivation of an oncoprotein is associated with differential attenuation rates of pro-survival and pro-apoptotic signals emanating from the oncoprotein, such that apoptotic signals become predominant and kill the cancer cell.

Differential signal decay

A signalling imbalance created by the rapid decay of pro-survival signals and persistence of the relatively long-lived pro-apoptotic signals after acute oncogene inactivation.

Gatekeeper residue

Amino acids with small side chains found at the catalytic site of enzymes that, when mutated to amino acids with bulkier side chains, can sterically impede the binding of a drug at the active site of the enzyme at the same time as retaining substrate binding.

Irreversible inhibitors

Inhibitors that bind covalently with biological molecules and interfere with their activity.

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Sharma, S., Bell, D., Settleman, J. et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7, 169–181 (2007). https://doi.org/10.1038/nrc2088

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