Understanding Drug Resistance in Lung Cancers Leads To Novel Treatment Combinations
Jeffrey Engelman, MD, PhD, scientific director of the Massachusetts General Hospital Cancer Center’s Center for Thoracic Cancer, and Pasi Jänne, MD, PhD, of the Lowe Center for Thoracic Oncology at Dana-Farber, an international research team of investigators from the DF/HCC, a Harvard Medical School consortium, have gained insight about how some lung cancers develop resistance over time to targeted therapies such as Iressa® (gefitinib) and Tarceva® (erlotinib). This new understanding of tumor resistance has led to the development of novel treatment combinations that may be useful in many different cancers.

Drugs like Iressa® and Tarceva® are used to treat non-small cell lung cancer (NSCLC), the leading cause of cancer deaths in the US. In 2004, researchers found that a portion of NSCLC patients responded rapidly and dramatically to these drugs. What they had in common was a common tumor mutation. In these patient tumors, the epidermal growth factor receptor (EGFR), a molecule on the cell membrane, was magnifying a potent signal that fueled tumor growth. Iressa® and Tarceva® specifically target EGFR, effectively starving the mutated tumors that rely on the molecule for growth.

Targeted therapies promised long-term hope for some patients with NSCLC. However, although tumors that respond to EGFR inhibitors do so quickly, eventually the tumors become resistant to the drugs and resume growth. In about half of the resistance cases a secondary mutation loosens Iressa’s bond and allows the cancer to circumvent the therapy.

Researchers are testing whether new drugs, called irreversible EGFR inhibitors, can prevent resistance in these tumors.
“We thought that if we could understand the resistance mechanism, we might be able to override it and extend the lives of these patients,” explains Engelman. He and his colleagues set out to discover what other unknown mechanisms would allow the resistant tumors to re-activate their growth pathways. They bathed tumor cells with mutant EGFR in Iressa® until the cells developed resistance and resumed growth, mimicking what happens in the body. Previously, the investigators had found that EGFR transmits its growth signal through a related protein called HER3 (or ERBB3) that initiates a potent growth pathway. Iressa blocks that pathway. Now, they discovered that MET amplification can also robustly activate HER3, creating an alternate route to the growth pathway. “About 20 percent of NSCLC patients become resistant because of the activity of a cancer-causing oncogene called MET that takes over for EGFR and fuels tumor growth,” explains Engelman, first author of the study, which was published in the journal Science in April 2007 and reviewed in the June Nature Medicine. “Importantly, we also identified a potential new way to treat these resistant tumors with combination therapy directed against both MET and the normal target of Iressa® ,” adds Jänne.

Analysis of tumor samples from 18 patients whose tumors became resistant after initially responding to Iressa revealed that MET was amplified in 4 of 18 patients. Blocking just MET or EGFR alone did not suppress the resistant cells’ proliferation. But combining MET and EGFR inhibitors both stopped growth signals and killed the tumor cells. “This method of reactivating the HER3 signaling pathway with MET may be a common resistance mechanism against other therapies that target receptors of the ERBB family, which are used against breast cancer, colon cancer, head and neck cancer and the brain tumor glioblastoma multiforme,” says Jänne. “Results from this study suggest why resistance occurs in some lung cancer patients and points to an obvious strategy for developing more effective therapies,” adds Engelman. To that end, researchers are now investigating the frequency of this resistance mechanism and are developing protocols that combine EGFR and MET inhibitors to treat NSCLC and other types of cancer. “There may be other resistance mechanisms we have yet to discover, but we have taken a significant step forward,” says Engelman.