Review
Oncogenes in non-small-cell lung cancer: emerging connections and novel therapeutic dynamics

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Summary

Non-small-cell lung cancer is a heterogeneous disease that is difficult to treat. Through efforts to define the molecular mechanisms involved in lung oncogenesis, molecularly targeted approaches for patients with lung cancer have now reached the clinical arena. Despite elucidation of some molecular mechanisms of lung carcinogenesis, prognosis for patients remains poor. This Review aims to highlight the functional associations between key oncogenes that drive lung tumorigenesis and are distinct targetable molecules. Oncogenes are defined by acquisition of mutations, which results in a dominant gain-of-function of the targeted protein. In this situation, a single mutated allele is sufficient to induce malignant transformation. Importantly, tumours become addicted to particular genetic alterations that cause oncogene activation and the continued expression of the signalling. An increasing amount of evidence sustains the rationale for targeting of oncogenic pathways rather than a single oncogene. A clear priority for both researchers and clinicians is to better understand the complexity of biological networks underlying lung cancer pathogenesis. This paradigmatic shift in tailoring therapies should effectively improve outcomes for patients.

Introduction

Cancer has a multi-step pathogenesis resulting from the progressive accumulation of genetic lesions that inactivate tumour suppressor genes or activate dominant proto-oncogenes.1 Nevertheless, use of classic genetics alone cannot account for the diversity of phenotypes within a cancer population that shares the same genotype; epigenetic and post-translational modifications of proteins are likely to have a crucial role in the aberrant process leading to cancer development, but they are generally not genetically driven and remain poorly understood.2

Lung cancer is the most common cause of death from solid tumours worldwide.3 Non-small-cell lung cancer (NSCLC) accounts for almost 80% of lung cancer diagnoses and encompasses different subtypes, among which adenocarcinomas and squamous-cell carcinomas account for almost 40% and 30% of cases respectively. NSCLC is characterised by a diverse collection of genomic alterations, and many pathogenetically important changes have already been detected in a substantial proportion of patients and been classified as disease biomarkers.4 Despite advances in our understanding of NSCLC molecules that are drug targets, the plasticity of cancer cells renders responses to targeted therapies transient, and allows short-term resistance to develop.

The aim of this Review is to provide a broad overview of the complex scenario of the still-evolving landscape of NSCLC,5 mainly focusing on the functional interplay between key oncogenes. These mechanisms are crucial in NSCLC onset and progression and are emerging as clinically relevant diagnostic and therapeutically actionable targets.

Section snippets

Oncogene addiction: the EGFR paradigm

Not all genetic damage that accumulates in cancer cells during tumour progression is equivalent—ie, mutations have different capacities and functions. Thus, certain mutations are more potent than others and become the driving force for tumour initiation and progression.6 Cancer cells are exclusively dependent on the activity of these particular mutated genes for their growth and survival. This concept is known as oncogene addiction, and reveals an Achilles' heel,7 or vulnerable point, which

Molecular profiling as a guide to therapy

The ability to interpret the molecular profiles of tumours is crucial for effective personalised treatment strategies.

The focus is therefore on a deeper understanding of cancer biology as well as the development of appropriate technologies to bring molecular testing to the clinical setting.

For NSCLC, EGFR-activating somatic mutations are the first example of predictive genetic markers of response to small tyrosine kinase inhibitors.16 Moreover, in the context of EGFR addiction, small tyrosine

Molecular lesions in squamous-cell carcinomas

Although several genetic lesions that characterise adenocarcinomas have been identified, much less is known about squamous-cell carcinomas (figure 2B). However, fibroblast growth factor receptor 1 (FGFR1), an important inducer of stromal responses and angiogenesis, might have a role. FGFR1 amplification is reported in about 16% of squamous-cell carcinomas.45 Although preliminary, these findings support a rationale for trials with FGFR1 inhibitors. PIK3CA is more frequently amplified in

Tumour heterogeneity

Somatic evolution, which drives tumour progression, is characterised by a complex mechanism that arises from the darwinian nature of the neoplastic process itself. Consequently, each individual tumour has a unique clonal architecture that is spatially and temporally heterogeneous; it results from an intricate interplay between genetic and non-genetic factors. Genetic factors are mainly linked to genomic instability, whereas non-genetic components result from differentiation hierarchies inside

Resistance in EGFR-mutated tumours

Phenotypic heterogeneity in tumour cell populations, despite creating an opportunity for selectivity, is one of the most important causes of therapeutic failure and disease relapse. The best recognised model of drug resistance involves genetic alterations, some of which can prevent a drug from binding to its target.

Primary resistance to a drug occurs when a genetic characteristic of the cancer cells prevents the drug from working. For example, not all EGFR mutations are associated with a

Clinical phenotypes identified by genetic lesions

Molecular profiling is contributing to improvements in tumour classification. Tumours with similar morphology can follow different clinical courses according to their mutational status. In NSCLC, EGFR mutations are known to occur preferentially in a restricted subset of patients—East Asian non-smoking women who have adenocarcinoma.10 Similarly, although less common, HER2 mutations are more likely in female non-smokers; they can coexist with either HER2 or EGFR gene amplification.74 By contrast,

Biology and applications of microRNA profiles

Modulation of gene expression is another key point for a more advanced personalised genetic approach. MicroRNAs are small, non-coding RNAs that control the translation and stability of mRNAs after transcription. Although in normal cells they regulate the expression of hundreds of genes and cooperate in maintenance of equilibrium in several biological processes, microRNAs can act as oncogenes or tumour suppressors. In addition, many oncogenes and tumour suppressor genes are potentially regulated

Therapeutic strategies for personalised therapy

The era of personalised medicine emphasises the concept that a tumour that arises in a patient is unique. However, tumour heterogeneity and the emergence of drug resistance seriously limit current therapeutic opportunities. The overall goal of current clinical research in oncology is to select the right patients for the right drugs. Patients with NSCLC are classified according to pathology, imaging, and molecular features, and the integration of the derived profile is the basis for the design

Outlook

A major shift in treatment of advanced NSCLC has occurred in recent years. New molecular targets are continually emerging, which highlights the complex biology that drives lung tumorigenesis. Although distinct subsets of oncogene-addicted NSCLC have been identified, therapeutic targeting of single oncogenic drivers has not identified a magic bullet.97 Although advances in genomics, molecular biology, tissue pathology, and imaging are providing the means to identify and investigate biomarkers of

Search strategy and selection criteria

We searched PubMed and Medline for the most relevant and recent studies on lung cancer biology and translational approaches. We also included knowledge from our own research and results. Data reported in supplementary tables were obtained by consulting PubMed from Jan, 2008, to Jan, 2013, to extract the most recent findings. Search terms included “EGFR” and “chemotherapy” for table 1 and “microRNA” and “lung cancer” for table 2. We also referred to online databases for detailed genetic and

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