Lung cancer is the leading cause of death among both men and women in the United States. Of the more than 220,000 new cases of lung cancer each year, roughly 5 percent has a specific abnormality in a gene called ALK. The gene rearrangement causes the ALK protein to have increased activity that can promote cell growth and lead to lung cancer. This small subset of patients can be treated with drugs that target ALK however, many patients fail to have their tumors disappear with these drugs or they develop acquired resistance to ALK inhibitors.

In a study published in Science Signaling, Moffitt Cancer Center researchers used proteomics to identify potential drug targets that could boost ALK inhibitors and improve patient outcomes. Proteomics is the study of proteins on a large scale and allows researchers to obtain vast amounts of data at one time.

Several drugs that block ALK activity have been approved to treat lung cancer patients who test positive for the ALK gene rearrangement. ALK inhibitors can shrink tumors and slow their growth.

Patients may become resistant to ALK inhibitors when their tumors develop a bypass mechanism that allows alternative survival and cell growth signals to become active despite the use of drugs that block ALK. "We wanted to develop a better picture of the ALK signaling landscape that can be used by researchers to develop improved therapeutic strategies for patient with ALK rearranged lung cancer. In addition, we wanted to use the power of advanced proteomics to define ALK signaling mechanisms so we could identify sensitizers to ALK inhibitors," said Eric B. Haura, M.D., leader of the Chemical Biology & Molecular Medicine Program and director of the Lung Cancer Center of Excellence at Moffitt.

Moffitt researchers have identified proteins and signaling pathways that sensitized lung cancer cells to ALK inhibitors.

The researchers found that ALK gene rearrangements orchestrated a network of over 460 proteins. They collaborated with colleagues at the University of Colorado to determine which of these proteins could sensitize lung cancer cells to ALK inhibitors. They reported that reducing the levels of 64 proteins could sensitize cells to the ALK inhibitor crizotinib, while reducing the levels of nine proteins could sensitize cells to the ALK inhibitor alectinib. Researchers focused on the adaptor proteins FRS2 and CC2D1A and showed that targeting either of these could sensitize multiple lung cancer cells lines to ALK inhibitors.

These results suggest that therapeutic strategies that interfere with adaptor proteins, such as FRS2 or CC2D1A, could be used to improve the activity of ALK inhibitors and potentially improve the treatment response.

"Our data set provides a resource that enhances our understanding of signaling and drug resistance networks consequent to ALK fusions and identifies potential targets to improve the efficacy of ALK inhibitors in patients," said Haura.

A podcast with Haura that further explains this study is available on the Science Signaling website. The project was supported by funds from the Moffitt Cancer Center SPORE in Lung Cancer (P50-CA119997), the Moffitt Lung Cancer Center of Excellence, the National Cancer Institute (R01-CA157850, P30-CA076292), the Moffitt Foundation, and the Colorado Lung Cancer SPORE in Lung Cancer (P50-CA058187).

Article: Coupling an EML4-ALK-centric interactome with RNA interference identifies sensitizers to ALK inhibitors, Guolin Zhang, Hannah Scarborough, Jihye Kim, Andrii I. Rozhok, Yian Ann Chen, Xiaohui Zhang, Lanxi Song, Yun Bai, Bin Fang, Richard Z. Liu, John Koomen, Aik Choon Tan, James Degregori, and Eric B. Haura, Science Signaling, doi: 10.1126/scisignal.aaf5011, published 18 October 2016.