Abstract
Cytotoxic chemotherapies are standard of care for patients suffering from advanced non‐small cell lung cancer (NSCLC). However, objective responses are only achieved in 20% of cases and long‐term survival is rarely observed. Clinically applied anticancer drugs exert at least some of their activities by inducing apoptosis. A critical step in apoptotic signal transduction is the permeabilization of the mitochondrial outer membrane (MOM), which is regulated by the BCL‐2 family of proteins. Hence, therapeutic targeting of BCL‐2 proteins is a promising approach to increase the drug‐sensitivity of cancers. To this end we have assessed the impact of conditional expression of the proapoptotic multidomain (BH1‐2‐3) protein BAK, which directly permeabilizes the MOM, and the BH3‐mimetic ABT‐737, which acts indirectly by derepressing BH1‐2‐3 proteins, on apoptosis and drug sensitivity of NSCLC cells. Conditionally expressed BAK sensitized resistant NSCLC cells to drug‐induced apoptosis. In contrast, ABT‐737 was ineffective in those NSCLC cells expressing high levels of the anti‐apoptotic MCL‐1 protein. Tissue microarray analysis of tumor samples from 84 chemotherapy‐naïve NSCLC patients revealed MCL‐1 expression in 56% of cases, thus supporting the relevance of this resistance factor in a clinical setting. Enforced expression of the BH3‐only protein NOXA, which targets MCL‐1, overcame resistance to ABT‐737. Moreover, combining conditionally expressed BAK with ABT‐737 enhanced apoptosis in NSCLC cells independently of their MCL‐1 status. In conclusion, the heterogeneity of apoptosis defects observed in drug‐resistant NSCLC demands individually tailored molecular therapies. Targeting the MOM permeabilizer BAK appears to have a broader apoptogenic activity than the BH3‐only mimetic ABT‐737. © 2007 Wiley‐Liss, Inc.