Researchers Find Protein That Could Combat Chemo Resistance in Lung Cancer and Mesothelioma

Pleural mesothelioma, an asbestos-caused cancer that affects the lining of the lungs, is highly aggressive and does not always respond to chemotherapy treatments. Both lung cancer and mesothelioma have proven to be chemo-resistant at times, rendering many of the chemotherapy treatments inadequate. Now, researchers report they  have identified a signaling protein in epidermal growth factor receptor positive lung cancer patients that could be targeted to conquer that resistance.

Researchers at Vanderbilt University set out to find a novel therapy that could combat cancer’s resistance to EGFR tyrosine kinase inhibitors therapies. They found that the signaling protein EPHA2 is overexpressed in EGFR tyrosine kinase inhibitors-resistant lung cancer cells and may be the cause for cancers becoming resistant.

The National Cancer Institute reports EGFR is a protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide. It is found at abnormally high levels on the surface of many types of cancer cells.  According to a 2009 article in Current Drug Targets, EGFR overexpression has been shown in more than 50% of pleural mesothelioma patients.

In 2011, the American Society of Clinical Oncology released a provisional clinical opinion stating patients with EGFR may benefit from treatment with EGFR-TKIs, such as, gefitinib (Iressa®, Astra Zeneca Pharmaceuticals) and erlotinib (Tarceva®, Genentech Inc). ASCO suggested oncologists check for an EGFR mutation before determining first-line therapy.

Although tumors with EGFR mutations “are initially extremely responsive to EGFR-specific tyrosine kinase inhibitors (TKIs),” per the Vanderbilt researchers, they eventually fail to respond.

“Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies,” according to the authors of the study, “EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer.”

However, they found that when the EPHA2 protein was blocked by another inhibitor the erlotinib-resistant tumor cells had reduced cell growth and increased cell death.

“These drug-resistant lung cancer cells were remarkably sensitive to EPHA2 blockage by a small molecule inhibitor, which decreased viability of cells with acquired resistance to a third generation TKI,” according to the Feb. 10 press release from Vanderbilt. “This suggests a potential method to overcome EGFR TKI resistance, and ultimately may lead to more effective mesothelioma treatments options for lung cancer patients.”

Lung cancer is the leading cancer killer for both men and women in the US, with approximately 160,000 Americans dying from the disease each year. Nearly 3,000 Americans are diagnosed with mesothelioma each year.

The study can be found in the Jan. 7 journal Cancer Research.
http://cancerres.aacrjournals.org/content/early/2012/04/25/0008-5472.CAN-11-3481.abstract

Sources:

• Vanderbilt University
  https://news.vanderbilt.edu/2016/02/10/overcoming-lung-cancer-resistance