As cancer cells adapt, drugs that worked well at first ultimately lose effectiveness. Patients move to more toxic drugs in an arms race against their own renegade cells. While therapies that target genetic alterations have significantly improved outcomes in several types of cancer, resistance continues to limit the effectiveness of promising therapies.
At Harvard Medical School, researchers in the lab of Joan Brugge, head of the Department of Cell Biology, are searching for strategies to overcome drug resistance in order for cancer patients to benefit fully from the potential of targeted therapies. Using a 3-D model of ovarian cancer developed in the Brugge lab, they have identified specific subpopulations of tumor cells that are resistant to drug-induced killing, determined how these tumor cells adapt to a promising drug attack, and identified drug combinations that defy drug resistance—providing insight for the direction of future cancer therapies.
In a study published Feb. 14 in the journal Cancer Cell, research fellow Taru Muranen and colleagues from the Brugge laboratory, in collaboration with Gordon Mills at MD Anderson Cancer Center in Houston, show that treatment with drugs targeting signaling pathways commonly altered in human carcinomas induces an adaptive response that confers drug resistance.
HMS Professor Joan Brugge and colleagues have studied drug resistance to PI3K and mTOR inhibitors (yellow dots) in 3D cell culture models of breast and ovarian cancer. Inner, matrix-deprived cells (red) undergo apoptosis while outer matrix-attached cells show adaptive resistance.
Activating mutations in the phosphoinositide 3-kinase (PI3K) pathway are commonly associated with many cancers and these mutations can drive tumorigenesis in cancer models through effects of tumor cell survival, metabolism and proliferation. Therefore, this pathway is a promising therapeutic target and many drug companies are developing drugs that block this pathway.
“Unfortunately, some tumors eventually relapse, often by activating an alternative pathway,” said Brugge, Louise Foote Pfeiffer Professor of Cell Biology and senior author on the paper. “Thus, single agent therapies may not be the most potent and effective treatments, since alternative pathways may be activated and lead to drug resistance.”
The Brugge lab group, using the 3-D model, observed that a subpopulation of tumor cells attached to extracellular matrix—which provides structural and other support to cells—resisted drugs that targeted PI3K/mTOR. While an anticancer drug killed cancer cells inside the model tumors, those on the surface, attached to the extracellular matrix, survived.
“The results suggest that cells attached to the extracellular matrix would survive drug treatment and contribute to relapse,” said Muranen, first author on the Cancer Cell paper. “Thus, it is critical to develop strategies to prevent or inhibit this adaptive response.”
Importantly, the Brugge group has found that treatment with a second drug that inhibits critical components of the adaptive response interrupted matrix protection and killed the matrix-attached cells. The combined treatment also caused much more effective tumor cell killing in a mouse model of ovarian cancer.
The research was funded in part by the Adelson Medical Research Foundation, which supports multidisciplinary research to prevent or treat life-threatening disease. “There are high hopes for the new generation of PI3K/mTOR-pathway inhibitors, but potential resistance to these drugs in epithelial cancers is a concern,” said Kenneth Fasman, vice president and chief scientific officer of the foundation. “Their model reveals that resistance is found only in subpopulations of tumor cells associated with the extracellular matrix, potentially explaining why these drugs are not uniformly effective on all cells in the tumor.”
The researchers are collaborating with drugmakers to explore therapies that inhibit this particular adaptive response. In the meantime, adaptive resistance remains a primary obstacle to effective cancer therapies.
—R. Alan Leo