Highlighting vulnerabilities in the alternative lengthening of telomeres pathway

The alternative lengthening of telomeres (ALT) pathway is a telomere elongation mechanism found in a small but often aggressive subset of cancers. Dependent on break-induced replication, telomere extension in ALT-positive cells relies on a baseline level of DNA replication stress to initiate elongation events. This results in an elevated level of DNA damage and presents a possible vulnerability to be exploited in the development of ALT-targeted cancer therapies. Currently, there are no treatment options that target the ALT mechanism or that are specific for ALT-positive tumors. Here, we review recent developments and promising directions in the development of ALT-targeted therapeutics, many of which involve tipping the balance towards inhibition or exacerbation of ALT activity to selectively target these cells.