Moving Beyond a Single Target

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Researchers show that protein portraits can predict outcomes for patients with lung cancer
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(L-R) First author Dr. Shideh Mirhadi and Drs. Michael Moran and Ming-Sound Tsao. Dr. Moran is an Affiliate Scientist at Princess Margaret Cancer Centre and senior co-author of the study. Dr. Tsao is a Senior Scientist at Princess Margaret Cancer Centre and Professor at the University of Toronto.

A research team co-led by Affiliate Scientist Drs. Michael Moran and Senior Scientist Dr. Ming-Sound Tsao at the Princess Margaret Cancer Centre has shown that laboratory models of lung cancer closely mirror the behavior of human tumours.

“Non-small cell lung cancer remains the leading cause of cancer deaths worldwide,” explains Dr. Tsao. “While there are several anti-cancer agents aimed at genetic mutations, most of the tumours do not harbor these targetable mutations and new effective anti-cancer agents are still much needed.” 

Using tumour samples from patients at the time of diagnosis and when cancer had returned, the research team implanted and successfully grew 137 tumours in laboratory models known as patient-derived xenografts. These models were established using two of the most common and aggressive types of lung cancer: adenocarcinoma and squamous cell cancer.

The research team then extensively studied the genetics and proteins present and used this information to construct molecular profiles of the tumours. Through analyzing the profiles, they found that the laboratory models closely mirrored human disease. The researchers also confirmed that the models had genetic mutations that are known to promote cancer cell growth, such as those in the KRAS and EGFR genes. Going further, the team looked at modifications to genes known as epigenetic changes that govern whether genes were turned on or off. These analyses also confirmed that laboratory models matched up with what is observed in human cancer.

“Because these models so closely mirror the profiles of human disease, they represent a gold-standard for testing the biology of deadly lung cancers,” explains co senior author Dr. Moran. “Taking this into account, we took a deep dive into the protein makeup, or proteotype, of lung cancer in our laboratory models. We did this to see if the set of proteins in these cancer models could provide new insight into human disease.” 

By comprehensively examining the proteins in the laboratory models, the research team discovered three adenocarcinoma and two squamous cell carcinoma proteotypes that were each associated with different patient outcomes.

In summarizing the findings Dr. Tsao said, “Our findings show that laboratory models not only closely reflect non-small cell lung cancer in patients, but they can also be used to provide new insight into treatment outcomes. Laboratory models can help us look more closely at the bigger picture—to consider genetics as well as the protein landscape—so that we can identify anti-cancer therapies that move beyond targeting single mutations.” 

This work was supported by the province of Ontario, the Canadian Cancer Society, the Canadian Institutes of Health Research, the Hospital for Sick Children (SickKids), the National Sciences and Engineering Research Council of Canada, the Terry Fox Foundation and The Princess Margaret Cancer Foundation.

Dr. Michael Moran is a Professor in the department of Molecular Genetics at the University of Toronto, a Senior Scientist at SickKids Research Institute, and an Affiliate Scientist at Princess Margaret Cancer Centre. At the University of Toronto, Dr. Tsao is the M. Qasim Choksi Chair in Lung Cancer Translational Research; and a Professor in the departments of Medical Biophysics, and Laboratory Medicine and Pathobiology. To access the PDX Finder resource please visit PMLB – PDXFinder.

Mirhadi S, Tam S, Li Q, Moghal N, Pham NA, Tong J, Golbourn BJ, Krieger JR, Taylor P, Li M, Weiss J, Martins-Filho SN, Raghavan V, Mamatjan Y, Khan AA, Cabanero M, Sakashita S, Huo K, Agnihotri S, Ishizawa K, Waddell TK, Zadeh G, Yasufuku K, Liu G, Shepherd FA, Moran MF#, Tsao MS#. Integrative analysis of non-small cell lung cancer patient-derived xenografts identifies distinct proteotypes associated with patient outcomes. Nat Commun. 2022 Apr 5;13(1):1811. doi: 10.1038/s41467-022-29444-9.  #joint supervisors of the research.

In 2021, nearly 30,000 Canadians were diagnosed with lung cancer, roughly 13% of all new cancer cases reported.