Resistance mechanisms to ALK TKIs in tumors other than lung cancer

The Anaplastic Lymphoma Kinase (ALK) was identified in 1994 as the C-terminal fusion partner in the chimeric protein arising from the recurrent t(2;5) translocation found in the anaplastic large-cell lymphoma (ALCL), a rare subgroup of T-cell malignancy. Since then, ALK has been involved in several additional tumors, both solid and hematological, through chromosomal rearrangements and activating point mutations. Following a spectacular success of targeted therapy in another fusion gene-driven cancer (chronic myeloid leukemia) a significant research effort has led to the development of several fairly selective ALK inhibitors. The use of such drugs is still investigational/compassionate (i.e., off-label) in ALK-dependent tumors other than lung cancer. Nevertheless, the activity of ALK inhibitors in ALK-positive ALCLs has been well documented, displaying high rates of long-term disease control. Despite excellent clinical activity, however, a significant fraction of patients still relapses after response, via both ALK-dependent (drug-resistant mutant clones) and ALK-independent (activation of alternative pathways) mechanisms. Moreover, different ALK-positive cancers show different responses to ALK inhibitors, likely reflecting different tumor biology, variable heterogeneity of the cancer cell population, as well as different co-dependencies to additional survival pathways, that will need to be targeted to achieve better therapeutic effects. Here, I reviewed the current literature on the involvement of ALK, the clinical activity of ALK inhibitors and the mechanisms of resistance to ALK inhibition in tumors other than non-small cell lung cancer.