Unlocking Pandora's box: personalising cancer cell death in non-small cell lung cancer

The mitochondria collectively represent a cellular Pandora's box. The key to effective treatment of non-small cell lung cancer (NSCLC) should be the identification of personalised therapeutic approaches capable of selectively engaging mitochondrial cell death. An approach that holds the greatest promise for achieving this may lie in the use of genetics to identify ‘keys to unlock’ Pandora's box in NSCLC.The organelles termed mitochondria constitute a major component of the canonical death pathway which initiates apoptosis. During life, these organelles play a critical role in maintaining bioenergetic homeostasis, predominantly through the synthesis of adenosine trisphosphate. However, following a fatal cellular insult, mitochondria commit irreversibility to ensuring the death of the cell. To achieve this, mitochondria release into the cytoplasm death-signalling proteins, which are normally harboured, safe out of reach, within the intermembrane space or cristae. This occurs as a result of mitochondrial outer membrane permeabilisation or MOMP. Upon release, these factors which include cytochrome C [1,2], OMI, smac [3], and apoptosis-inducing factor [4,5] lead to the activation of cellular demolition machinery comprising zymogens termed caspases, which systematically cause the noninflammatory elimination of the cell via apoptosis and immune cell engulfment [6]. MOMP occurs as a result of the activation of proapoptotic BCL2 family proteins.The multidomain family members BAX and BAK exhibit genetic redundancy and undergo homo- and hetero-oligomerisation [7,8] to promote pore formation in the outer mitochondrial membrane — essentially the key to unlocking Pandora's box [9]. To trigger MOMP, BAX/BAK must first be activated. This requires a subset of proapoptotic BCL2 family proteins which harbour a single BCL-2 homology domain 3 (BH3) [10-13]. This alpha helical amphipathic domain is sufficient to activate BAX and BAK and may do so by two mechanisms. The BH3-only proteins