Introduction: Protein kinases are involved in various cellular functions including metabolism, cell cycle regulation, survival, and differentiation. Dysregulation of protein kinases is implicated in various processes of carcinogenesis. The advent of protein kinase inhibitors in cancer therapy has led to a paradigm shift in how we treat cancer. There are several protein kinase inhibitors that have been approved by FDA in the last few decades. Areas Covered: This article provides a review of the clinical benefits and side effect profiles of FDA approved protein kinase inhibitors as of December 2017 for the well-known oncogenic protein kinases. The role of the respective oncogenic protein kinases in carcinogenesis and cancer progression were searched in PubMed and discussed. The relevant and landmark clinical trials mostly phase III trials of protein kinase inhibitors leading up to the FDA approval were PubMed searched and discussed. Expert Commentary: Further understanding of the molecular origin of cancers would help us identify new targets, while clinical trials trying to identify the appropriate sequence of available kinase inhibitor would make better use of current protein kinase inhibitor armamentarium. Also, testing these drugs in the adjuvant setting in patients with high risk of recurrence might offer some clinical benefit. Development of resistance, side effects and cost are major limitations of protein kinase inhibitors, therefore understanding of the molecular mechanisms of resistance and designing protein kinase inhibitors to obviate the resistance would help overcome the resistance. Finally, collaboration between international organizations for cancer research and voluntary and charity organizations might help reduce the cost.

Matched-targeted and immune checkpoint therapies have improved survival in cancer patients, but tumor heterogeneity contributes to drug resistance. Our study categorized gene mutations from next generation sequencing (NGS) into three core processes. This annotation helps decipher complex biologic interactions to guide therapy. We collected NGS data on 145 patients who have failed standard therapy (2016 to 2018). One hundred and forty two patients had data for tissue (Caris MI/X) and plasma cell-free circulating tumor DNA (Guardant360) platforms. The mutated genes were categorized into cell fate (CF), cell survival (CS), and genome maintenance (GM). Comparative analysis was performed for concordance and discordance, unclassified mutations, trends in TP53 alterations, and PD-L1 expression. Two gene mutation maps were generated to compare each NGS platform. Mutated genes predominantly matched to CS with concordance between Guardant360 (64.4%) and Caris (51.5%). TP53 alterations comprised a significant proportion of the mutation pool in Caris and Guardant360, 14.7% and 13.1%, respectively. Twenty-six potentially actionable gene alterations were detected from matching ctDNA to Caris unclassified alterations. The CS core cellular process was the most prevalent in our study population. Clinical trials are warranted to investigate biomarkers for the three core cellular processes in advanced cancer patients to define the next best therapies.