Old TKI may find new purpose: Combat specific aggressive cancers

The multi-targeted tyrosine-kinase inhibitor (TKI) ponatinib appears to be active against a subset of cancers characterized by the presence of cells positive for alternative lengthening of telomeres (ALT), a team of Singapore-based investigators has found.

In a study, the team conducted an anticancer compound library screen on isogenic cell lines and using extrachromosomal telomeric C-circles, which served as a marker of ALT activity. Ponatinib deregulated ALT mechanisms, induced telomeric dysfunction, and reduced ALT-associated telomere synthesis. [Nat Commun 2023;14:1919]

The findings were confirmed in in vitro experiments wherein ponatinib treatment in osteosarcoma and liposarcoma cells led to DNA damage, dysfunctional telomeres, and the triggering of senescence. Additionally, telomere synthesis in the cells slowed down after 18 to 20 hours of treatment.

“The effects of ponatinib on cell death of ALT cells and their telomeric C-circles was not limited to sarcoma but was also observed in ALT glioma stem cells,” the investigators noted.

Likewise, results of in vivo experiments showed that mice with ALT-positive tumours treated with ponatinib had a reduction in the levels of their telomeric C-circles as compared with untreated mice.

“Using RNA-sequencing and quantitative phosphoproteomic analyses, combined with C-circle level assessment, we find an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing telomeric C-circles,” the investigators said.

“Furthermore, transcriptome and interactome analyses suggest a role for JUN in DNA damage repair. These results are corroborated by synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors, such as triciribine,” they added.

Achilles heel of ALT cancers

“A prominent feature of cancer is its ability to evade cell death and acquire indefinite replication—to stay immortal, in other words—which it can do through the ALT mechanism. While a sizeable portion of cancer cells depend on this mechanism, there is no clinically approved targeted therapy available,” according to lead investigator Dr Maya Jeitany from the Nanyang Technological University School of Biological Sciences.

“Through our study, we identified [ABL1-JNK-JUN], a novel signalling pathway in the ALT mechanism, and showed that the FDA-approved drug ponatinib inhibits this pathway and holds exceptional promise in stopping the growth of ALT cancer cells,” Jeitany stated.

ALT is present in about 10–15 percent of all cancers and is especially prevalent in several tumour types, such as osteosarcoma, soft tissue sarcoma, and glioblastoma. Jeitany believes that their work may pave a therapeutic avenue for ALT cancers and provide a repurposing opportunity for a clinically approved anticancer drug indicated for certain patients with chronic myeloid leukaemia or Philadelphia chromosome-positive acute lymphoblastic leukaemia. [Am J Pathol 2011;179:1608-1615]

 Jeitany and colleagues have already taken the next step in their research by examining how ponatinib affects telomeres to understand in greater detail the ABL1-JNK-JUN signalling pathway. Potential ponatinib-based combination treatments for ALT cancers are also being assessed.