An improved understanding of these gene alterations is needed in order to assist in the identification of new therapeutic targets leading to improved clinical outcomes. This will require translational laboratory research to establish underlying oncogene addiction. Despite the complexity of the molecular biology of NSCLC, a vast array of new targets for NSCLC drug

treatments are being investigated (Table 2), including HER2 and HER3. Although HER2 receptor overexpression occurs in around 30% of NSCLCs, the results of trials with anti-HER2 agents have not been encouraging [71] and [72]. As phosphorylation of EGFR is frequently through Natural Product Library HER3 [73], addition of an anti-HER3 drug to improve the efficacy of anti-EGFR agents has also been investigated, and trials to investigate this strategy are ongoing. KRAS is a frequent

mutation in lung cancer tumours that was previously thought to be undruggable; however, recent studies suggest alternative ways of targeting this mutation. One such strategy involves inhibition of cyclin-dependent kinase 4 (CDK4), since KRAS appears to be dependent on this cell cycle progressing molecule in animal models [74]. Inhibition of MEK has also been investigated, with a progression-free survival (PFS) benefit being demonstrated for the MEK inhibitor, selumetinib, when used in combination with docetaxel in patients with KRAS mutant tumours Navitoclax [75]. The latter findings should be treated with caution, however, as the effects of this agent in KRAS wild-type or an unselected population is unknown. Nevertheless, recent preclinical data provide support for the combination of MEK and BCL-XL inhibition as a strategy for targeting KRAS [76]. Immunotherapeutic strategies are also being investigated, and encouraging results have been demonstrated for the anti-cytotoxic T-cell lymphocyte-4 monoclonal antibody, Meloxicam ipilimumab, when

used in combination with paclitaxel and carboplatin as first-line therapy in patients with stage III NSCLC [77]. Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T-cells, has also been examined as a strategy to overcome immune resistance and mediate tumour regression [78], though selection of the subpopulation of patients who will benefit from this strategy will be challenging. There is a need for improved trial designs for the development of new targeted agents for NSCLC, particularly when targeting rare and infrequent mutations like DNA repair deficiencies, with studies including assessment of biomarkers and involving selected populations. Ideally, new drugs should be investigated initially in the metastatic setting before earlier settings are studied, with development targeting the non-smoking population in the first instance to maximise response.