Experimental Determination of Cancer Drug Targets with Independent Mechanisms of Resistance

• Published in: Current cancer drug targets Vol. 22; no. 2; p. 97
• Main Authors: Bland, Abigail R, Shrestha, Nensi, Berry, Maddie, Wilson, Christabel, Ashton, John C
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2022
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Drug Combinations; Drug Resistance, Neoplasm; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mutation; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; ALK; lung cancer; drug targets; mathematical modelling; drug resistance; combination treatment
• ISSN: 1873-5576
• DOI: 10.2174/1568009622666220107152014

Mathematical modelling of tumour mutation dynamics has suggested that cancer drug targets that have different resistance mechanisms should be good candidates for combination treatment. This is because the development of mutations that cause resistance to all drugs at once should arise relatively infrequently. However, it is difficult to identify drug targets fulfilling this requirement for particular cancers. Here we present four experimental criteria that we argue are necessary (but not sufficient) conditions that drug combinations should meet in order to be considered for combination drug treatment aimed at delaying or overcoming cancer drug resistance. We present the results of our own experiments - guided by these criteria - using anaplastic lymphoma kinase mutated lung cancer cells. Each set of experiments demonstrate results for different drug combinations. We conclude that the combination of ALK and MEK inhibitors come closest to meeting all our criteria.