The RAS/RAF/MEK/ ERK and the PI3K/AKT/mTOR pathways govern fundamental physiological processes, such as cell
proliferation, differentiation, metabolism, cytoskeleton reorganization and cell death and survival. Constitutive activation of these signal
transduction pathways is a required hallmark of cancer and dysregulation, on either genetic or epigenetic grounds, of these pathways has
been implicated in the initiation, progression and metastastic spread of lung cances. Targeting components of the MAPK and PI3K cascades
is thus an attractive strategy in the development of novel therapeutic approaches to treat lung cancer, although the use of single
pathway inhibitors has met with limited clinical success so far. Indeed, the presence of intra- and inter-pathway compensatory loops that
re-activate the very same cascade, either upstream or downstream the point of pharmacological blockade, or activate the alternate pathway
following the blockade of one signaling cascade has been demonstrated, potentially driving preclinical (and possibly clinical) resistance.
Therefore, the blockade of both pathways with combinations of signaling inhibitors might result in a more efficient anti-tumor effect,
and thus potentially overcome and/or delay clinical resistance, as compared with single agent. The current review aims at summarizing
the current status of preclinical and clinical research with regard to pathway crosstalks between the MAPK and PI3K cascades in
NSCLC and the rationale for combined therapeutic pathway targeting.