黑料网 Lineberger researchers find how triple negative breast cancer cells are able to bypass treatment with trametinib, an FDA-approved drug. The researchers also used lab models of breast cancer to test a potential treatment approach that could prevent resistance.
黑料网 Lineberger researchers, including senior author, Gary L. Johnson, PhD, Kenan distinguished professor in the Department of Pharmacology, first author, Jon Zawistowski, PhD, research assistant professor in the Johnson lab, and co-first author, Samantha Bevill, graduate student in the Johnson lab have found how triple negative breast cancer cells are able to bypass treatment with trametinib, an FDA-approved drug. The researchers also used lab models of breast cancer to test a potential treatment approach that could prevent resistance. Their findings were published in this week.
Breast cancer cells are evasive, finding ways to bypass drugs designed to stop their unchecked growth. In a new study, researchers uncovered a mechanism of resistance used by a particularly aggressive breast cancer type, and revealed a possible drug combination that could stop cancer growth and also help to prevent resistance.
鈥淭umor cells are extremely adaptive and responsive. When you treat patients with kinase inhibitors there is often a strong initial arrest of tumor growth, but, invariably, resistance develops,鈥� said Gary L. Johnson. 鈥淲hat we found is that tumor resistance to this type of drug involves what we call 鈥榓daptive reprogramming鈥� of the genome. But we learned how to arrest the adaptive reprogramming and make the tumor remain vulnerable to the drug. Thus, we blocked the onset of resistance.鈥�
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| Jon Zawistowski, PhD, Research Assistant Professor, Johnson lab member and first author on the paper |
Johnson and his colleagues used advanced genetic sequencing technologies to uncover how triple negative cancer cells developed resistance to the kinase inhibitor trametinib. Targeted therapies, like trametinib, are designed to block specific signaling pathways that are overactive or abnormal in cancer. However, cancer cells can change the expression of genes in alternative protein pathways in order to skirt around the blocked pathway, allowing them to restart uncontrolled cell growth.
In particular, triple negative breast cancer cells treated with trametinib altered their genetic landscape by forming several thousand new 鈥渆nhancers鈥� 鈥� DNA sequences that help to turn on specific genes. The enhancers are bound by molecules, such as one called BRD4, that help to turn on genes.
To see if they could reverse the changes that were causing resistance, they tested an investigational drug that blocks BRD4鈥檚 ability to induce the formation of new enhancers that drove the genetic changes involved in resistance to trametinib. They found that pairing the investigational anti-BRD4 drug with trametinib helped to stop tumor growth in experiments in cells and in mouse models.
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| Samantha Bevill, Graduate Student, Johnson Lab member and co-first author on the paper. |
To make sure their findings about the mechanism of resistance were relevant in actual breast cancers, the researchers examined triple negative breast cancer samples from women participating in a clinical trial led by 黑料网 Lineberger member , physician-in-chief of the N.C. Cancer Hospital and the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research. In that trial, women with newly diagnosed triple negative breast cancer allowed biopsies of their cancers before and after one week of treatment with low doses of trametinib. Johnson and his colleagues found that their prediction of resistance to these drugs from laboratory models held true in the human breast cancers, lending further support to approaches they are developing to prevent this resistance.
鈥淎s a clinician, I have to also say that this kind of collaboration, in which brilliant scientists partner directly with doctors and cancer patients to examine our thorniest problems is the roadmap for how we can deliver great ideas into the clinic quickly,鈥� Carey said.
In addition to Carey, Johnson, Zawistowski, and Bevill, other authors include: Daniel R. Goulet, Timothy J. Stuhlmiller, Adriana S. Beltran, Jose F. Olivares-Quintero, Darshan Singh, Noah Sciaky, Joel S. Parker, Naim U. Rashid, Xin Chen, James S. Duncan, Martin C. Whittle, Steven P. Angus, Sara Hanna Velarde, Brian T. Golitz, Xiaping He, Charlene Santos, David B. Darr, Kristalyn Gallagher, Lee M. Graves, Charles M. Perou and H. Shelton Earp.