Cancer stem cells and their acquired resistance to cancer drugs are the subject of investigation in a study co-authored by researchers at University of California San Diego and University of Texas MD Anderson Cancer Center. “There are a number of drugs that patients respond to during their initial cancer treatment, but relapse occurs when cancer cells become drug-resistant,” explained David Cheresh, PhD, principal investigator of the study at UCSD Moores Cancer Center, in a press release from UCSD. In the study published in Nature Cell Biology, “We looked at the cells before and after they became resistant and asked, ‘What has changed in the cells?'”
To answer this question, Cheresh and colleagues chose to look at integrin αvβ3 on the surface of breast, lung, and pancreatic tumor cells due to its association with poor outcome and increased risk for metastasis in patients whose tumors express the receptor. What they found is that αvβ3 becomes upregulated on cancer cells when they are exposed to receptor tyrosine kinase inhibitors such as erlotinib and lapatinib, which are standard cancer treatment drugs. Integrin αvβ3 was then able to initiate a membrane-proximal complex with KRAS and RalB to activate TBK1 and NF-κB. In other words, the signaling mechanism enhanced anchorage independence, self-renewal, tumor initiation, and receptor tyrosine kinase inhibitor resistance of cancer cells.
“The good news is that we’ve uncovered a previously undefined pathway that the tumor cells use to transform into cancer stem cells and that enable tumors to become resistant to commonly used cancer drugs,” said Dr. Cheresh. By elucidating the pathway, the team knew how they might be able to reverse the stem-like features of the cancer cells and reverse drug resistance: combine erlotinib treatment with bortezomib, an agent that is clinically approved for myeloma. In fact, when they treated with both agents, tumors were completely depleted of the drug resistant αvβ3-expressing cells.
Already, Hatim Husain, MD, from Moores Cancer Center, has designed a clinical trial around the results of this study. Next year, the trial will be open to patients with lung tumors resistant to erlotinib; hopefully in the future, the study will open up to include patients with early-stage cancer to prevent drug resistance. “Resistance builds to targeted therapies against cancer, and we have furthered our understanding of the mechanisms by which that happens,” said Dr. Husain. “Based on these research findings we now better understand how to exploit the ‘Achilles heel’ of these drug-resistant tumors. Treatments will evolve into combinational therapies where one may keep the disease under control and delay resistance mechanisms from occurring for extended periods of time.”
University of Texas, MD Anderson Cancer Center co-authors on the study included Tina Cascone, Lixia Diao, Jing Wang, Ignacio I. Wistuba and John V. Heymach.