A large fraction of non-small cell lung cancers (NSCLC) are dependent on defined 
oncogenic driver mutations. Although targeted agents exist for EGFR- and 
EML4-ALK-driven NSCLCs, no therapies target the most frequently found driver 
mutation, KRAS. Furthermore, acquired resistance to the currently targetable 
driver mutations is nearly universally observed. Clearly a novel therapeutic 
approach is needed to target oncogene-driven NSCLCs. We recently showed that the 
basic helix-loop-helix transcription factor Twist1 cooperates with mutant Kras 
to induce lung adenocarcinoma in transgenic mouse models and that inhibition of 
Twist1 in these models led to Kras-induced senescence. In the current study, we 
examine the role of TWIST1 in oncogene-driven human NSCLCs. Silencing of TWIST1 
in KRAS-mutant human NSCLC cell lines resulted in dramatic growth inhibition and 
either activation of a latent oncogene-induced senescence program or, in some 
cases, apoptosis. Similar effects were observed in EGFR mutation-driven and 
c-Met-amplified NSCLC cell lines. Growth inhibition by silencing of TWIST1 was 
independent of p53 or p16 mutational status and did not require previously 
defined mediators of senescence, p21 and p27, nor could this phenotype be 
rescued by overexpression of SKP2. In xenograft models, silencing of TWIST1 
resulted in significant growth inhibition of KRAS-mutant, EGFR-mutant, and 
c-Met-amplified NSCLCs. Remarkably, inducible silencing of TWIST1 resulted in 
significant growth inhibition of established KRAS-mutant tumors. Together these 
findings suggest that silencing of TWIST1 in oncogene driver-dependent NSCLCs 
represents a novel and promising therapeutic strategy.