Targeting ALT Cancers Via Replication Stress at Telomeres

Scientists have discovered novel synthetic lethal interactions could be harnessed to target alternative lengthening telomere (ALT) cancers in the future.

ALT cancers rely on homologous recombination to maintain their telomere length. They are more susceptible to replication stress, and chemotherapy is the only treatment option available for ALT cancers.

Although numerous cancers that reproduce via telomerase reactivation have other treatment options than chemotherapy, ALT cancer cells lack telomerase.

In a study published in the Proceedings of the National Academy of Sciences, investigators sought to gain a better understanding of ways to inhibit ALT cancer growth to identify potential new treatment options.

The investigators examined 3 human genes associated with cancer development. FANCM mutations are associated with blood cancers, BRCA1 mutations are associated with breast and ovarian cancers, and BLM mutations can cause various cancers.

When FANCM was removed from cells that also lacked BRCA1 or BML, the investigators found the simultaneous inactivation of BLM and FANCM or BRCA1 and FANCM cause a dramatic increase in DNA damages that prevented cancer cells from continuing to proliferate.

“In creating a more stressful replication environment at the site of ALT telomeres, cellular reproduction was halted, leading us to believe that there could be great potential for these novel synthetic lethal therapeutic strategies,” said author Dong Zhang, PhD. “Therefore, we recommend further exploring this possibility to target ALT cancers.”

The findings suggest that if drugs are developed to suppress BLM and FANCM, or BRCA1 and FANCM, it could serve as a therapeutic option for ALT cancers without the toxicity commonly found with standard chemotherapy drugs.

“We propose that these synthetic lethal interactions can be explored for targeting the ALT cancers,” the authors concluded.