Broad Resistance Mechanism to Targeted Drugs, Chemotherapies
By Anette Breindl
While searching for mechanisms of resistance to one targeted cancer therapy, researchers have identified a signaling mechanism that can lead to resistance to multiple targeted and chemotherapy cancer drugs alike.
Loss of the protein MED12 activates signaling of transforming growth factor beta, or TGF-beta. And "that activation of TGF-beta signaling can cause resistance to... a broad range of cancer drugs: both targeted therapies as well as chemotherapies," Rene Bernards told BioWorld Today.
Bernards is at the Netherlands Cancer Institute and the senior author of the paper describing the discovery, which was published in the Nov. 22, 2012, issue of Cell.
Bernards and his team were looking for resistance mechanisms to one particular drug, namely the targeted lung cancer therapy Xalkori (crizotinib, Pfizer Inc.). Like many targeted cancer drugs, Xalkori comes out of the gate strong but often soon falters, as tumors develop resistance.
Resistance is not, however, limited to targeted cancer therapies. Chemotherapy, too, can lose its effectiveness as tumors develop resistance. And while the resistance mechanisms to targeted drugs can be identified, in many cases, through molecular analysis, "chemotherapy resistance has been nearly impossible to predict," Bernards said.
Even in targeted therapies, resistance can be caused by mutations that activate alternate pathways, rather than directly affecting the binding of the drug to its target. Bernards and his team were searching for such mutations through an RNAi knockdown screen, and found that when cancer cells lost MED12, they became resistant to ALK inhibitors, including Xalkori, but also EGFR inhibitor Iressa (gefitinib, AstraZeneca plc.).
When Bernards and his team tested cell lines to see just how broad the effect of MED12 on drug resistance was, they found that knockdown influenced the response to multiple drugs used to treat multiple tumor types. In addition to Xalkori, MED12 knockdown interacted with selumetinib (AZD6244/ARRY-886), Nexavar (sorafenib, Onyx Pharmaceuticals Inc. and Bayer AG) and Zelboraf (vemurafenib, Roche AG).
To top it off, MED12 knockdown also conferred resistance to several chemotherapies, including cisplatin and 5-fluoruracil.
The team next looked for a common mechanism that might account for the broad effects of MED12 knockdown. They found that MED12 normally inhibits the signaling of one type of TGF-beta receptor, TGF-betaR2. When MED12 expression is lost, that receptor is up-regulated, leading to downstream effects on signaling pathways that are also influenced by many receptor tyrosine kinases.
TGF-beta signaling through Type II receptors also appears to set off a change in cells that is known as the epithelial-to-mesenchymal transition, or EMT. The EMT, in which cells go from a more differentiated to a less differentiated and more stem-like state, has been implicated in both metastasis and drug resistance. (See BioWorld Today, July 11, 2007.)
MED12 is part of a larger complex that regulates transcription. But its effects on TGF-beta signaling happen in the cytoplasm, and knocking down other members of the mediator complex had no effect on drug sensitivity or resistance, leading Bernard and his team to conclude that its effects on drug resistance are not due to any actions of the larger complex.
On the scientific side, Bernards said, "our finding that EMT causes chemoresistance may offer an avenue to study chemotherapy resistance, which is what we are following up upon right now."
The findings also have practical implications. The studies were done in collaboration with Dutch biotech Agendia BV. Agendia, Bernards said, "plans on developing a predictive gene signature based on this publication. We are already in discussions with pharma partners to use the identified signature in clinical trials."
And in terms of therapeutic options, "we see that about 30 percent of colon cancers have undergone an epithelial-to-mesenchymal transition, similar to what is induced by MED12 suppression. These . . . tumors do not respond to chemotherapy. If this EMT is caused by TGF-beta signaling, as we think is the case, then addition of a TGF-beta inhibitor should restore the response to chemotherapy, a testable hypothesis. Also," he added, "many lung cancers develop resistance to EGFR-targeted therapy by undergoing EMT; again a TGF-beta inhibitor could help prevent this."
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