A newly discovered multi-kinase inhibitor, 108600, showed promise against resistant triple negative breast cancer (TBNC) in a mouse model and human cell studies.

"We [screened] for novel agents that target a population of cells that drive treatment resistance, rather than targeting a single molecule or pathway," Dr. Hanna Irie of the Icahn School of Medicine at Mount Sinai in New York City told Reuters Health by email. "Cancer cells often use multiple pathways to survive and resist treatment, so blocking a single molecule is likely not going to be as effective against TNBC cancers, which often have very complex genetic profiles."

"We hope to translate our findings to a clinical trial in the next 3-5 years," she said. "We are actively working towards optimizing the administration method of 108600 to efficiently reach sites of cancer in the body."

"We are excited about this compound, as it is effective in models of established TBNC metastases, a scenario that simulates stage 4 patient disease," she said. "So we are hopeful that it can help patients living with advanced TNBC."

As reported in Nature Communications, 108600 is a novel multi-kinase inhibitor that targets the TNBC breast cancer stem cell (BCSC) population. The teams' experiments showed that 108600 treatment suppressed the growth, colony- and mammosphere-forming capacity of BCSCs and induced G2M arrest and TNBC apoptosis.

In vivo, 108600 treatment of mice with triple negative tumors resulted in the induction of apoptosis and overcame chemotherapy resistance.

Further experiments showed that treatment with 108600 and chemotherapy suppressed the growth of pre-established TNBC metastases.

Specifically, the research showed:

• - 108600 induced apoptosis of paclitaxel-resistant TNBCs in vitro.

• - 108600 acted synergistically with paclitaxel in mouse models of TBNC that were resistant to the drug, even when tumors were not responsive to paclitaxel as a single agent.

"This observation is particularly significant since chemotherapy resistance remains a critical problem facing patients diagnosed with TNBC," the authors state.

• - 108600 was an effective suppressor of established metastases when given in combination with paclitaxel in studies with LM2-4 cells, a highly metastatic variant of the MDA-MB-231 cell line. "This property of 108600 may prove to be highly advantageous to patients with advanced TNBC whose cancers are resistant to chemotherapy," the authors note.

The authors conclude, "108600 's efficacy against established metastatic disease and its favorable toxicity profile make it a promising therapeutic for clinical translation."

Dr. Irie said, "We are next studying the effects that 108600 has on the interaction between TBNC and immune cells. There is evidence that cancer stem cells evade recognition by the immune system, allowing them to persist. We think that by eliminating cancer stem cells with 108600, we can promote a healthier anti-cancer immune response and improve efficacy of immunotherapies."

SOURCE: https://go.nature.com/3s4pQWa Nature Communications, online August 3, 2021.