Protein kinase inhibitors in metastatic colorectal cancer. Let's pick patients,tumors, and kinase inhibitors to piece the puzzle together!

Introduction: Increased understanding in intracellular signaling pathways leading to carcinogenesis, proliferation, migration, invasion, angiogenesis, and anti-apoptosis of colorectal cancer cells has been critical for target identification and drug development. Specific protein kinase inhibitors (KIs) have been developed to block activated pathways associated with tumor growth and progression. Although showing promising activity in preclinical models, until now, the majority of KIs were not able to demonstrate clinically meaningful efficacy in Phase II/III trials.

Areas covered: The major pathways altered in colorectal cancer will be highlighted, and molecularly defined targets will be discussed. The mechanisms of action and the proof of principle demonstrated in preclinical models of KIs and the disappointing efficacy in clinical trials will be reviewed.

Expert opinion: Despite recent negative study results, KIs have the potential to be the next class of therapeutics in the treatment of metastatic colorectal cancer. Molecular classification of the individual tumors and identification of molecular escape mechanisms for primary (intrinsic) and secondary resistances to KI treatment is critical to select the patients' most likely to benefit. Appropriate drug combinations based on those mechanisms of resistance have to be tested in selected patient populations to ensure progress and efficacy with the goal to lead to a clinically meaningful prolongation of patients' lives.