Scientists develop a two-step approach to starve lung tumor cells

signaling, xinhuanet.com reported.

IGF-1 signaling is a pathway that inÀuences the uptake and release of nutrients and ultimately cell growth, according to the researchers.

Nada Kalaany, a researcher in Boston Children’s Hospital and the paper’s senior author, said, “Growth factors like IGF-1 tell cells that nutrients are around, so when you suppress their signaling, the tumor cells don’t take up the amino acids.”

Kalaany’s team used two groups of mice with Kras-driven lung cancer. The second group has been deleted with two key genes, known as Irs1 and Irs2, which encode so-called ‘adaptor’ proteins that are necessary for insulinigf-1 signaling.

Kalaany said, “Almost all animals in this lung cancer model typically die within 15 weeks of KRAS activation.

“But the ones that lost both Irs1 and Irs2 were completely ¿ne, we saw almost no tumors at 10 to 15 weeks.”

Metabolic pro¿ling revealed that tumor cells lacking Irs1-2 had signi¿cantly lower levels of essential amino acids, the building blocks of protein. Yet, outside the cells, amino acids were plentiful.

But that’s not the whole story. When tumor cells ‘think’ that they are starved, according to Kalaany, they can compensate for this and break down their own proteins to generate amino acids.

The researchers tried to inhibit the protein breakdown with existing drugs, such as chloroquine, which inhibits autophagy, and bortezomib, a proteasome inhibitor that is used to treat multiple myeloma.

When Kalaany’s team injected human tumor cells lacking Irs1/2 into mice, tumors didn’t grow as well. When they added inhibitors of protein breakdown, growth was almost completely suppressed.

She said, “Our work tries to identify metabolic dependencies and vulnerabilities in tumors.”

However, Kalaany warned that, though both types of drugs, as well as IGF-1 inhibitors, are well tolerated, care would need to be taken in dosing any combination therapy to avoid toxicities.