Hitting the nail on the head: overcoming therapeutic resistance in lung cancer

A protein highly expressed in lung cancer cells drives resistance to targeted therapies, report researchers at the Medical University of South Carolina in the Journal of Thoracic and Cardiovascular Surgery. In preclinical experiments, the researchers showed that inhibiting the protein caused the death of non-small cell lung cancer cells that had become resistant to therapy.

The MUSC Team was led by Chadrick E. Denlinger, M.D., who was then surgical director of the Lung Transplant Program at MUSC Health, and MUSC Hollings Cancer Center researcher Robert Gemmill, Ph.D., who is a professor emeritus in the Department of Medicine. Denlinger is now division chief of thoracic surgery at Indiana University but continues his collaboration with Gemmill.

Lung cancer accounts for a quarter of all cancer deaths, and non-small cell lung cancer makes up 84% of all lung cancer cases. Targeted therapies can be effective for a time against selected lung cancers, but resistance to these therapies soon develops.

A cancer cell is like a small factory with many moving parts working towards one common goal: survival and reproduction of the tumor at the expense of the patient.

A type of targeted drug, called a tyrosine kinase inhibitor, or TKI, works by inhibiting a specific, vital piece of machinery within the cell factory on which it is dependent. However, the factory has many fail-safes in place and can quickly rely on another piece of cellular machinery to continue to grow and survive, even in the presence of the TKI. The ability of a cancer cell to adapt to a new strategy to survive is called “genetic resistance.”

When researchers developed TKIs for the treatment of cancers such as non-small cell lung adenocarcinoma (NSCLC), they had hoped they would become the “magic bullet” to treat the disease successfully.

“One of the benefits of TKIs is that they’re much less toxic and are fairly beneficial — we see a dramatic response and the tumors shrink,” said Denlinger. “But a limitation is that these effects don’t last very long before the cancer cells evolve new techniques to become resistant to the drug.”

Due to such resistance, the survival outcomes for patients receiving TKIs are no better than those for patients receiving conventional chemotherapy. Consequently, the need to find treatments that can overcome that resistance is urgent.

Gemmill’s group, which includes Cecile Nasarre, Ph.D., Anastasios Dimou, M.D., and a summer undergraduate, Rose Pagano, recently linked drug resistance in lung cancers to the expression of a cell surface co-receptor Neuropilin 2 (NRP2). Gemmill received pilot project funds from the South Carolina Clinical & Translational Research Institute for his work with NRP2.

“One of the earliest things we discovered was that the NRP2 variant protein, NRP2b, dramatically increased in lung cancer patients who became resistant to therapy,” remarked Gemmill. “This gave us the first clue that it becomes upregulated in resistant tumors.”

The investigators then performed a series of experiments in which they “knocked down” NRP2b from lung cancer cell lines that were capable of developing TKI resistance.

“When we knock down NRP2b, we lose the surviving drug-tolerant cells,” said Gemmill. “And by reducing that population, we believe we will reduce the ability of the tumor to develop genetic resistance.”

Next, they explored how NRP2b could be contributing to drug resistance in lung cancer cells. They started with GSK3, a molecule that’s involved in many different activities within the cell and has been reported previously to interact with NRP2b during neuronal development. The investigators performed experiments to determine whether NRP2b interacts with GSK3B.

“You can think about GSK3B as a hammer,” said Gemmill. “And this hammer has the job of hammering many different nails that are present in the cell. NRP2b is like the hand of the carpenter that directs that hammer to particular nails. NRP2b is using GSK3B as a hammer to drive very specific nails, and we want to stop that because those nails are driving tumor progression.”

To better understand the specific nails that NRP2b and GSK3B are driving in lung cancer, the investigators performed experiments in which they measured how well lung cancer cells can migrate and survive in the presence of TKIs in the absence of these two players. With these experiments, they found that NRP2b needs GSK3B to promote cancer cell migration, an essential step in cancer progression, and drug resistance.

Now that the investigators have identified a mechanism by which cancer cells are becoming resistant to treatment, their next step will involve developing inhibitors. More specifically, they will try to develop inhibitors that interfere with the carpenter (NRP2) grabbing the hammer (GSK3B).

“Importantly, these inhibitors should not interfere with other functions of GSK3B, which will reduce potentially harmful off-target effects in a healthy cell,” said Denlinger.

Currently, the team is working to test the toxicity and effectiveness of prototype drugs that could specifically disrupt the interaction between GSK3B and NRP2b. They are collaborating on this work with MUSC College of Pharmacy researchers Patrick M. Woster, Ph.D., chair of the Department of Drug Discovery & Biomedical Sciences, and associate professor Yuri K. Peterson, Ph.D.

“Ultimately we could find a way to improve therapy for cancer patients,” said Denlinger. “A therapy that could extend the influence of TKIs and potentially reduce metastatic spread and extend the lives of patients.”

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Dr. Gemmill, Dr. Cecile Nasarre and Dr. Peterson have patents pending for mimetic peptides for the treatment of cancer.

About MUSC

Founded in 1824 in Charleston, MUSC is the oldest medical school in the South, as well as the state’s only integrated, academic health sciences center with a unique charge to serve the state through education, research and patient care. Each year, MUSC educates and trains more than 3,000 students and nearly 800 residents in six colleges: Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy. The state’s leader in obtaining biomedical research funds, in fiscal year 2019, MUSC set a new high, bringing in more than $284 million. For information on academic programs, visit musc.edu.

As the clinical health system of the Medical University of South Carolina, MUSC Health is dedicated to delivering the highest quality patient care available, while training generations of competent, compassionate health care providers to serve the people of South Carolina and beyond. Comprising some 1,600 beds, more than 100 outreach sites, the MUSC College of Medicine, the physicians’ practice plan, and nearly 275 telehealth locations, MUSC Health owns and operates eight hospitals situated in Charleston, Chester, Florence, Lancaster and Marion counties. In 2019, for the fifth consecutive year, U.S. News & World Report named MUSC Health the No. 1 hospital in South Carolina. To learn more about clinical patient services, visit muschealth.org.

MUSC and its affiliates have collective annual budgets of $3.2 billion. The more than 17,000 MUSC team members include world-class faculty, physicians, specialty providers and scientists who deliver groundbreaking education, research, technology and patient care

About MUSC Hollings Cancer Center

MUSC Hollings Cancer Center is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center comprises more than 100 faculty cancer scientists and 20 academic departments. It has an annual research funding portfolio of more than $44 million and a dedication to reducing the cancer burden in South Carolina. Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques within multidisciplinary clinics that include surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer care, including more than 200 clinical trials. For more information, visit http://www.hollingscancercenter.org

About the SCTR Institute

The South Carolina Clinical and Translational Research (SCTR) Institute, a National Institutes of Health Clinical and Translational Science Awards hub, is the catalyst for changing the culture of biomedical research, facilitating sharing of resources and expertise, and streamlining research-related processes to bring about large-scale, change in the clinical and translational research efforts in South Carolina. Our vision is to improve health outcomes and quality of life for the population through discoveries translated into evidence-based practice. For more information, visit https://research.musc.edu/resources/sctr.