Mechanism Of Cell Death In Cancers Treated With Epidermal Growth Factor Receptor Inhibitors

Main Category: Cervical Cancer / HPV Vaccine
Article Date: 29 Oct 2007 - 17:00 PDT

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Three papers published this month in the open access general medical journal PLoS Medicine investigate how tumors respond to a an important class of drugs used in cancer chemotherapy, known as epidermal growth factor receptor (EGFR) inhibitors.

EGFR plays a critical role in the control of cellular proliferation, differentiation, and survival. Abnormalities in signaling of the EGFR pathway have been found in a wide range of cancers, including carcinomas of the lung, breast, and colon. Inhibitors of EGFR such as gefitinib are used in the treatment of these cancers, particularly non-small cell lung cancers which have mutations within the EGFR gene. However, the exact molecular mechanisms leading to tumor response to these drugs has been unclear.

The three independent studies with lead authors William Pao from Memorial Sloan Kettering, New York, Andreas Strasser from the Walter and Eliza Hall Institute Australia, and Susumu Kobayashi from Beth Israel Deaconess Medical Center, Boston, each investigated this pathway and show that that one protein, BIM, a member of a class of proteins that leads to apoptosis (programmed cell death) is essential for tumor cell killing by drugs such as gefitinib in cells with EGFR mutations. These results suggest that induction of BIM may in future lead to a way of treating tumors that have developed resistance to these drugs.

The papers are further discussed in a perspective by Ingo Mellinghoff from UCLA.

Citation: Gong Y, Somwar R, Politi K, Balak M, Chmielecki J, et al. (2007) Induction of BIM Is Essential for Apoptosis Triggered by EGFR Kinase Inhibitors in Mutant EGFR-Dependent Lung Adenocarcinomas. PLoS Med 4(10): e294
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Citation: Cragg MS, Kuroda J, Puthalakath H, Huang DCS, Strasser A (2007) Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med 4(10): e316.
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Citation: Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS, et al. (2007) BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med 4(10): e315.
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Related PLoS Medicine Perspective:

Citation: Mellinghoff I (2007) Why do cancer cells become "addicted" to oncogenic epidermal growth factor receptor? PLoS Med 4( 0): e321
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