Glioma—it's all in the site occupancy

Hutchinson, Lisa

doi:10.1038/nrclinonc.2012.65

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Published: 17 April 2012

Targeted therapies

Glioma—it's all in the site occupancy

Lisa Hutchinson

Nature Reviews Clinical Oncology volume 9, page 308 (2012)Cite this article

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Activating mutations in EGFR occur in glioblastoma multiforme (GBM) and lung cancer; however, only patients with lung cancer have shown a clear response to EGFR inhibitors. Two studies published in Cancer Discovery shed light on the reasons behind these contrasting observations.

Ingo Mellinghoff and coauthors examined established GBM cell lines and freshly derived tumour sphere lines to assess EGFR mutations. “Our finding that EGFR activity is critical for the survival of EGFR mutant GBM cells suggests that inadequate EGFR inhibition, rather than redundancy in GBM signalling networks, may be the principal cause of drug resistance,” explains Mellinghoff. He continues, “another important and unexpected finding was the differential sensitivity of GBM versus lung cancer EGFR mutants to EGFR kinase inhibitors. Inhibitors such as lapatinib or neratinib, which stabilize the kinase in the inactive conformation, were considerably more potent than erlotinib at inhibiting the extracellular EGFR mutants found in GBM.” Interestingly, the researchers found that the opposite was true for the most common EGFR kinase domain mutations in lung cancer, which were inhibited more effectively by drugs such as erlotinib that stabilize the active conformation.

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ORIGINAL RESEARCH PAPERS

Vivanco, I. et al. Differential sensitivity of glioma-versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov. doi:10.1158/2159-8290.CD-11-0284
Barkovich, K. J. et al. Kinetics of inhibitor cycling underlie therapeutic disparities between EGFR-driven lung and brain cancers. Cancer Discov. doi:10.1158/2159-8290.CD-11-0287

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