(Chemo)resistance Is Futile

While late diagnosis remains a key reason for the dismal outcome of pancreatic ductal adenocarcinoma (PDAC), the fact that it is difficult to treat using non-surgical methods also presents a big problem. PDAC tumors are often resistant to chemotherapy; only two agents are currently approved to treat advanced disease. The first, gemcitabine, increases median survival by just over one month (from 4.41 to 5.65 months) compared with the previously used drug, 5-fluorouracil (1). Adding the second, erlotinib, has an even smaller effect – increasing survival by only one-third of a month (2). Despite the many Phase III trials conducted to improve the efficacy of chemotherapy – using everything from traditional chemotherapy to experimental targeted approaches – PDAC remains stubbornly resistant to treatment (3).

Why? Because very few patients ever experience a good response to chemotherapy, we know that PDAC’s resistance to treatment is primary (innate), rather than secondary (acquired) as in most other cancers – but what we haven’t known is what gives rise to this resistance. One research team from the University of Texas MD Anderson Cancer Center pointed the finger at the epithelial-to-mesenchymal transition (EMT). The EMT program plays a role in metastasis, but the researchers noticed that when cancer cells begin to migrate, they stop proliferating. Lead author Raghu Kalluri explained that “gemcitabine works primarily on cancer cells that are dividing or proliferating. When cancer cells suspend their proliferation – such as when they launch an EMT program – then anti-proliferation drugs like gemcitabine do not target them well,” (4).

To examine the role of EMT in PDAC, Kalluri and his colleagues generated mouse models of PDAC that featured a deletion of either Snail or Twist – two transcription factors responsible for the EMT program. Deleting either of those proteins had no effect on tumor pathology, invasion or metastasis, but it did increase cancer cell proliferation and gemcitabine sensitivity (5). “We found that the EMT program suppressed drug transporter and concentrative proteins, which inadvertently protected these cancer cells from anti-proliferative drugs, such as gemcitabine,” said Kalluri – so suppressing the influence of that program resulted in a stronger response to chemotherapy, including reduced tumor burden and significantly better survival. What does this mean for patients? No research has been conducted yet in humans, but the promising results in mice indicate that EMT suppression may be an intriguing target worthy of further investigation.

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