Collateral sensitivity networks reveal evolutionary instability and novel treatment strategies in ALK mutated non-small cell lung cancer.
Drug resistance remains an elusive problem in cancer therapy, particularly with novel targeted therapy approaches. Much work is currently focused upon the development of an increasing arsenal of targeted therapies, towards oncogenic driver genes such as ALK-EML4, to overcome the inevitable resistance that develops as therapies are continued over time. The current clinical paradigm after failure of first line ALK TKI is to administer another drug in the same class. As to which drug however, the answer is uncertain, as clinical evidence is lacking. To address this shortcoming, we evolved resistance in an ALK rearranged non-small cell lung cancer line (H3122) to a panel of 4 ALK tyrosine kinase in-hibitors used in clinic, and performed a collateral sensitivity analysis to each of the other drugs. We found that all of the ALK inhibitor resistant cell lines displayed a significant cross-resistance to all other ALK inhibitors. To test for the stability of the resistance phenotypes, we evaluated the ALK-inhibitor sensitivities after drug holidays of varying length (1, 3, 7, 14, and 21 days). We found the resistance patterns to be stochastic and dynamic, with few conserved patterns. This unpredictability led us to an expanded search for treatment options for resistant cells. In this expansion, we tested a panel of 6 more anti-cancer agents for collateral sensitivity among the resistant cells, uncovering a multitude of possibilities for further treatment, including cross-sensitivity to several standard cytotoxic therapies as well as the HSP-90 inhibitors. Taken together, these results imply that resistance to targeted therapy in non-small cell lung cancer is truly a moving target; but also one where there are many opportunities to re-establish sensitivities where there was once resistance.