Resistance to anaplastic lymphoma kinase inhibitors: knowing the enemy is half the battle won

Anaplastic lymphoma kinase (ALK) translocations are responsible of neoplastic transformation in a limited subset of non-small cell lung cancer (NSCLC) patients. In recent years outcomes of these patients improved due to the development and clinical availability of specific and extremely active targeted therapies [i.e., next-generation Tyrosine Kinase Inhibitors (TKI)]: ALK+ patients are now reaching impressive results when treated with more potent inhibitors upfront with an average median progression-free survival (mPFS) around 35 months. However, under drug pressure, cancer cells develop resistance and patients eventually progress. Multiple mechanisms of intrinsic or acquired resistance have been extensively characterized. Less potent ALK inhibitors (ALKi)—like crizotinib—usually tend to induce a large spectrum of secondary intra-kinase mutations; however, these alterations may be observed also after sequential administration of multiple ALKi. Noteworthy, neoplastic cells may evade ALK targeting through a myriad of different mechanisms involving cell-stroma interaction, activation of parallel signaling pathways, intracellular downstream adaptation and histological reshaping, as relevant molecular events. Often these phenomena are restricted to a limited number of cases or even can be patient-specific, thus hindering the development of therapeutic strategies largely applicable. Consequently, the recognition of specific resistance mechanisms seldom translates in clinical opportunities. Management of ALK+ patients is drastically changed and deciphering the molecular biology underlying this disease during treatment is of paramount relevance. The bedrock of resistance to TKI is that, after the diagnosis, we face with a different disease that needs to be re-characterized through tissue or/and liquid biopsies. Understanding molecular pathways driving the resistant phenotype will give us the chance to know what we are dealing with and, rather than choose an empirical approach, will help us to properly define the best targeted treatment for these patients.