Personalized cancer medicine: molecular diagnostics, predictive biomarkers, and drug resistance

Abstract

The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution.

Figure 1

Chemical structures of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and their molecular modes of binding to the target. (a) Two-dimensional (2D) structure of reversible inhibitor gefitinib and the three-dimensional (3D) structure in complex with EGFR (PDB code 3UG2). (b) 2D structure of reversible inhibitor erlotinib and the 3D structure of the binding site of EGFR in complex with erlotinib (PDB code 4HJO). (c) 2D structure of the potent irreversible inhibitor afatinib (BIBW-2992) and the 3D structure of the binding site of EGFR in complex with afatinib, showing the covalent interaction with Cys797, highlighted in orange (PDB code 4G5J). PDB, Protein Data Bank.

Figure 2

Biochemical pathways leading to resistance to small-molecule epidermal growth factor receptor (EGFR)-targeting drugs such as gefitinib and erlotinib in non-small-cell lung cancer (NSCLC). Simplified pathway diagram showing EGFR signaling through the RAS/MEK/ERK and PI3K/PDK1/AKT pathways, illustrating the points of mutation/amplification in EGFR TKI resistance, along with other mechanisms. The resistance mechanisms include the EGFR p.T790M gatekeeper mutation, amplification of EGFR p.T790M, MET amplification, PI3KCA mutation, and an at least two-fold increase in the expression of GAS6 and its receptor AXL. Incidence rates are given where known. The FAS/nuclear factor-κB (NF-κB) signaling arm downstream of the FAS death receptor has also been shown to be important in EGFR tyrosine kinase inhibitor resistance. In addition, epithelial-to-mesenchymal (EMT) transition changes, perhaps associated with increased activity of AXL, and transformation from the NSCLC to the small-cell lung cancer (SCLC) phenotype can lead to decreased responsiveness. The identification of various resistance mechanisms suggests that a range of clinically actionable therapies could be used to overcome the resistance. For more details, see text.

Figure 3

Envisaging the future of personalized precision medicine for cancer treatment. Future approaches will be based on adaptive therapy in response to information from tumor profiling using multiple technologies, including next-generation sequencing to identify predictive and resistance biomarkers, and incorporating analyses of clonal, morphological, and anatomical heterogeneity and their variations longitudinally in real time.