Personalized targeted therapy for lung cancer

Abstract

Lung cancer has long been recognized as an extremely heterogeneous disease, since its development is unique in every patient in terms of clinical characterizations, prognosis, response and tolerance to treatment. Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment. In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets. This review covers the basic mechanism of EGFR and EML4-ALK activation, the predictive biomarkers, the mechanism of resistance, and the current targeted tyrosine kinase inhibitors. The efficacy of EGFR and ALK targeted therapies will be discussed in this review by summarizing the prospective clinical trials, which were performed in biomarker-based selected patients. In addition, the revolutionary sequencing and systems strategies will also be included in this review since these technologies will provide a comprehensive understanding in the molecular characterization of cancer, allow better stratification of patients for the most appropriate targeted therapies, eventually resulting in a more promising personalized treatment. The relatively low incidence of EGFR and ALK in non-Asian patients and the lack of response in mutant patients limit the application of the therapies targeting EGFR or ALK. Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients.

Keywords: ALK; EGFR; biomarker; lung cancer; next-generation sequencing.

Figure 1

Epidermal growth factor receptor (EGFR). The binding between EGFR and ligand triggers downstream intracellular signaling pathways including the PI3K/AKT prosurvival, STAT transcription, and RAS/RAF/MEK proliferation pathways. The anaplastic lymphoma kinase (ALK) fusion proteins mainly activate the RAS/RAF/MEK and PI3K/AKT pathways. Amplification of the EGFR and ALK signaling pathways drives cell proliferation, cell motility, and carcinogenesis.

Figure 2

The frequency of EGFR mutations. The deletion of exon 19 nested located between residues 747–750, which are mainly composed of delGlu746-Ala750, delGlu746-Ser752insVal, delLeu747-Thr751, delLeu747-Ser752, and delLeu747-Pro753insSer.