The Molecular Mechanisms and Therapeutic Prospects of Alternative Lengthening of Telomeres (ALT)

SIMPLE SUMMARY: This review summarizes the current understanding of the telomere maintenance mechanism known as the Alternative Lengthening of Telomeres (ALT). The role, recognizable indicators, and proposed mechanism of the ALT pathway in sustaining cancer cells are reviewed. Potential molecular targets for future therapeutic development are proposed with the goal of synthesizing the current understanding of the ALT pathway that will be required to make future advances in ALT cancer treatments. ABSTRACT: As detailed by the end replication problem, the linear ends of a cell’s chromosomes, known as telomeres, shorten with each successive round of replication until a cell enters into a state of growth arrest referred to as senescence. To maintain their immortal proliferation capacity, cancer cells must employ a telomere maintenance mechanism, such as telomerase activation or the Alternative Lengthening of Telomeres pathway (ALT). With only 10–15% of cancers utilizing the ALT mechanism, progress towards understanding its molecular components and associated hallmarks has only recently been made. This review analyzes the advances towards understanding the ALT pathway by: (1) detailing the mechanisms associated with engaging the ALT pathway as well as (2) identifying potential therapeutic targets of ALT that may lead to novel cancer therapeutic treatments. Collectively, these studies indicate that the ALT molecular mechanisms involve at least two distinct pathways induced by replication stress and damage at telomeres. We suggest exploiting tumor dependency on ALT is a promising field of study because it suggests new approaches to ALT-specific therapies for cancers with poorer prognosis. While substantial progress has been made in the ALT research field, additional progress will be required to realize these advances into clinical practices to treat ALT cancers and improve patient prognoses.