Study reveals cellular mechanisms driving resistance to targeted cancer therapies

Despite impressive innovations in medicine, most advanced-stage cancers still carry a grim prognosis. Developing more effective treatments requires a deeper understanding of the cellular processes that drive the formation and growth of common cancers.

In a new study, published May 19 in the AAAS journal Science Signaling, researchers from Harrington Discovery Institute at University Hospitals provide a new understanding of the processes that drive cancer and identify promising targets for treatments identified in human cancer cell models and corroborated in human cancers.

The new findings from the research team, led by Seth J. Field, MD, PhD, Director, Physician-Scientist Programs and Chief Scientific Officer, Harrington Discovery Institute, could help address one of the biggest challenges in oncology: overcoming resistance to existing targeted therapies.

This work builds on our previous studies identifying components of the cellular machinery, specifically involving the Golgi apparatus, that enable cells to transport material to their surface where it can remain or be released,"

Dr. Seth J. Field, MD, PhD, Director, Physician-Scientist Programs and Chief Scientific Officer, Harrington Discovery Institute

Analysis of human cancers had previously identified components of this Golgi secretory machinery as contributors to common cancers, including lung, breast and colorectal cancers. However, their exact role remained unclear.

"We found that, in their normal function, these proteins assist the movement of growth factor receptors to the cell surface," Dr. Field said. "Once there, these receptors are activated by growth factors in the cellular environment, signaling cells to grow uncontrollably and form tumors."

Growth factor receptors are well-established drivers of many cancers. The epidermal growth factor (EGF) receptor, for example, plays a key role in lung cancer, while HER2 is involved in many breast cancers. Many modern therapies are designed to interfere with these receptors, often with good effect. However, in most patients, cancers eventually become resistant to these treatments.

By identifying new cellular components required for growth factor signaling, the researchers have uncovered a new class of therapeutic targets that may complement existing therapies.

"Discoveries in fundamental biology are the fuel that enables advances in medicine," Dr. Field added. "The next step in our research involves working to develop potential therapeutics that build on this discovery."

These therapeutics will be developed with the support of Harrington Discovery Institute, which has a singular mission: accelerating promising discoveries into medicines that address unmet needs. Now in its 13th year, the institute's growing portfolio includes 227 medicines in development, support for 75 institutions, 46 companies launched, 24 medicines in clinical trials, and 15 licenses to pharmaceutical partners.

Dr. Field also holds the Harrington Endowed Chair for Scientific Director and is the Becky Hennessy Endowed Master Clinician in Breast Cancer Genomics. He is also a senior attending physician and professor of medicine and endocrinology at UH Cleveland Medical Center and Case Western Reserve University School of Medicine, and a member of the Case Comprehensive Cancer Center.