New Pathway Responsible for Resistance to Chemotherapy Uncovered

Researchers at Harvard Medical School and the Massachusetts General Hospital Cancer Center in Boston have identified a new cellular pathway that is at least partly responsible for slow proliferation of cancer cells. Slowly dividing cancer cells are problematic because they are difficult to kill with cytotoxic agents--including chemotherapy.

The results are published in Molecular Cancer Research, a journal of the American Association for Cancer Research.

“We have identified a new pathway in which well-studied signaling molecules string together to regulate cell proliferation,” said Sridhar Ramaswamy, MD, an associate professor of medicine at Massachusetts General Hospital Cancer Center and Harvard Medical School.

Several of the molecules in the new pathway are well-studied and being evaluated as therapeutic targets.

The authors are now working on ways to target this pathway in animal models to understand whether there is potential for clinical applications. 

Tumors are made up of rapidly dividing cells, which are killed by chemotherapy, and slowly dividing ones that are more difficult to eradicate as these typically remain after such treatment. These slowly dividing cells are also more difficult to detect and contribute to disease recurrence.

From laboratory studies, researchers have observed that while replication typically produces two fast-dividing progeny cells, sometimes cell division results in slow-dividing tumor cells. But the circumstances of how and when these types of cells emerge are not understood.

Ramaswamy and colleagues identified a pathway involving Beta1-integrin, FAK, mTORC2, and AKT1 that can switch rapidly dividing cells to undergo asymmetrical division to produce slowing proliferating daughter cells with low AKT1 expression. A previous study showed that asymmetrical suppression of AKT prior to cell division--one of the two emerging daughter cells-has low levels of AKT and proliferates slowly. These slow dividing tumor cells with low AKT expression have been identified in breast cancer patients. These cells were resistant to the combination chemotherapy used to treat the patients.

In the current study, the authors investigated how two daughter cells with differing AKT1 protein levels-and different proliferation indices-emerge.

“Prior to these studies, we thought that asymmetric suppression of AKT might just relate to random fluctuations in protein levels during cell division,” said Ramaswamy in a statement. “We discovered that this is not the case; it is actually regulated by a potentially targetable signaling pathway, which may offer new avenues for reducing the proliferative heterogeneity within tumors for therapeutic effect.”

The current study delineated some of the molecular mechanisms of this asymmetrical cell division. In the laboratory, decreasing levels of the cell surface protein beta1-integrin resulted in decreased signaling through the intracellular protein FAK, and subsequently, to an uptick in the activity of a complex that includes the mTORC2 protein. Higher levels of mTORC2 then result in suppression of AKT1 protein levels through the proteasome and the TTC3 molecule.

“Deeper insight into these molecular interactions, the precise cellular contexts in which they occur, and why cancer cells retain this functional pathway for producing slow proliferators may thus provide further useful insight into cancer biology,” stated the authors. 

“[The current findings] reveal that proliferative heterogeneity within cancer cell populations, in part, is produced through a targetable signaling mechanism, with potential implications for understanding cancer progression, dormancy, and therapeutic resistance,” concluded Ramaswamy and colleagues.