ALK Gene Alterations in Cancer: Biological Aspects and Therapeutic Implications

Abstract

ALK was first reported in 1994 as a translocation in anaplastic large cell lymphoma and then described with different abnormalities in a number of tumors. Recently, a shortly accumulated biomedical research clarified the numerous biological processes underlying its ability to support cancer development, growth and progression. Advent of precision medicine has finally provided unexpected advances, leading to the development of ALK-targeting inhibitors with superior efficacy as compared with standard chemotherapy regimens, as well as the identification of resistance mechanisms and the creation of 'next-generation' treatments. This review summarizes the current understanding of ALK-driven cancers from the oncogenesis and mutation frequency by The Cancer Genome Atlas database through the diagnostic approach, to an updated portrait of available tyrosine kinase inhibitors, considering their effectiveness in cancer treatment, the molecular reasons of therapeutic failure, and the actual and future ways to overcome resistances.

Pediatric Non-Myofibroblastic Primitive Spindle Cell Tumors with ALK Gene Rearrangements and Response to Crizotinib

“…Regardless of the partner gene, the breakpoints in ALK usually occur at intron 19 and always retain the kinase domain (encoded by exons 20-29) at the 3′ end, which then fuses with the 5′ end including the promoter of the fusion partner gene. 45,46 Likewise, ALK exons 20-29 are retained and in frame in the CLTC::ALK and PLEKHH2::ALK fusions reported here (Figures 4 and 8). While the ALK kinase domain appears to be necessary for oncogenic function of the fusion protein, the partner genes appear to dictate the cellular localization (nuclear or cytoplasmic) of the fusion protein and may also affect treatment responses.…”

“…While the ALK kinase domain appears to be necessary for oncogenic function of the fusion protein, the partner genes appear to dictate the cellular localization (nuclear or cytoplasmic) of the fusion protein and may also affect treatment responses. 45,46 The two tumors presented here illustrate the diagnostic and therapeutic value of RNA sequencing of pediatric malignancies. In a study examining the additional diagnostic yield of RNA sequencing compared to conventional methods such as FISH or RT-PCR, 52% of the patient samples (12 of 23) that were negative by conventional methods had a fusion gene identified by RNA sequencing.…”

“…While the ALK kinase domain appears to be necessary for oncogenic function of the fusion protein, the partner genes appear to dictate the cellular localization (nuclear or cytoplasmic) of the fusion protein and may also affect treatment responses. 45,46…”

Dramatic response to crizotinib in a breast cancer patient with ALK gene rearrangement

“…Moreover, oncogenic activation of ALK via fusions, amplification, or activating point mutations accompanying ALK , can be seen in other cancer types. Therefore, the question arose whether ALK inhibitors would be effective in a broader landscape [3,4].…”