Research Article: Why Do Cancer Cells Become “Addicted” to Oncogenic Epidermal Growth Factor Receptor?

Date Published: October 30, 2007

Publisher: Public Library of Science

Author(s): Ingo Mellinghoff

Abstract: The author discusses three new studies in PLoS Medicine that shed light on the mechanisms involved in apoptosis triggered by EGFR kinase inhibitors.

Partial Text: During the last five years, kinase inhibitors have emerged as a promising new class of cancer therapeutics [1]. These drugs target enzymes that are often ubiquitously expressed within the human body, control a wide range of cellular responses, and are tightly regulated under physiological conditions [2]. Cancer cells can escape these normal restraints on kinase activity through mutations in kinase-encoding genes or genes regulating their function [3]. Even though tumorigenesis is a multistep process requiring multiple genetic aberrations, cancer cells can become so dependent on, or “addicted” to, a deregulated signaling pathway that blocking this signal results in cell death [4]. Oncogene addiction was first documented in genetically engineered mouse models of cancer [5–7] and subsequently proven in the clinic by the dramatic response of BCR-ABL–positive leukemias to the small molecule ABL-kinase inhibitor imatinib [8,9].

To study the mechanisms of EGFR TKI-induced cell death, all three research teams took advantage of the large number of NSCLC cell lines that have been characterized in terms of their EGFR mutational status and cytotoxic response to the EGFR TKIs gefitinib and erlotinib: H3255, PC-9, and HCC827 cell lines showed the most dramatic apoptotic responses; H1975, A549, and H460 cells were resistant; and H1650 cells showed an intermediate response. Cell death in response to EGFR kinase inhibition featured cytochrome c release and activation of BAX and could be rescued by overexpression of BCL-xL, all consistent with activation of the mitochondrial “intrinsic” pathway of apoptosis.

Using RNAi technology and cells from gene-targeted mice, Junya Kuroda et al. recently demonstrated that BIM (and to lesser degree BAD) play a critical role in imatinib-induced apoptosis of BCR-ABL–positive leukemia cells [20]. The current studies demonstrate that activation of the intrinsic cell death pathway through induction of BIM is also required to elicit an apoptotic response to EGFR TKIs in NSCLC cells harboring mutant EGFR. While this observation remains to be formally proven in patients, it should be emphasized that the preclinical models used in these studies have a strong track record of predicting drug response and drug resistance in patients with NSCLC and EGFR mutations [13,21–24]. The current studies thus raise the question whether mutations in the intrinsic cell death pathway provide a mechanism of resistance to EGFR TKIs and perhaps other kinase inhibitors.



Leave a Reply

Your email address will not be published.