Scientists from the University of California, San Diego School of Medicine say they discovered a biomarker called CD61 on the surface of drug-resistant tumors that appears responsible for inducing tumor metastasis by enhancing the stem cell-like properties of cancer cells.

The study (“An integrin β3–KRAS–RalB complex drives tumour stemness and resistance to EGFR inhibition”), published in Nature Cell Biology, may point to new therapeutic opportunities for reversing drug resistance in a range of cancers, including those in the lung, pancreas, and breast, according to the scientists.

“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, Ph.D., distinguished professor of pathology and UC San Diego Moores Cancer Center associate director for Innovation and Industry Alliances. “We looked at the cells before and after they became resistant and asked, 'What has changed in the cells?'”

He and his colleagues investigated how tumor cells become resistant to drugs like erlotinib or lapatinib, known as receptor tyrosine kinase inhibitors and commonly used in standard cancer therapies. They found that as drug resistance occurs, tumor cells acquire stem cell-like properties that give them the capacity to survive throughout the body and essentially ignore the drugs.

Specifically, the scientists delineated the molecular pathway that facilitates both cancer stemness and drug resistance, and were able to identify existing drugs that exploit this pathway. These drugs not only reverse stem cell-like properties of tumors, but also appear to resensitize tumors to drugs to which the cancer cells had developed resistance.

“We reveal [in vitro and in mice] that integrin αvβ3 serves as a marker of breast, lung, and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase [RTK] inhibitors such as erlotinib,” wrote the investigators. “αvβ3, in the unliganded state, recruits KRAS and RalB to the tumor cell plasma membrane, leading to the activation of TBK1 and NFκB. In fact, αvβ3 expression and the resulting KRAS–RalB–NFκB pathway were both necessary and sufficient for tumor initiation, anchorage independence, self-renewal, and erlotinib resistance. Pharmacological targeting of this pathway with bortezomib reversed both tumor stemness and erlotinib resistance. These findings not only identify αvβ3 as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy to sensitize such tumors to RTK inhibition.”

“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,” continued Dr. Cheresh. The team has designed a clinical trial to attack this pathway in patients whose tumors are drug resistant.

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