Susanna Fletcher Greer, Chief Scientific Officer at The V Foundation, shared on LinkedIn:
“If you follow cancer research (and clearly you are cool and you do because you’re here), you’ve probably heard a lot about KRAS lately, particularly in pancreatic cancer. For decades, KRAS was one of those cancer drivers that we understood was enormously important but struggled to target with drugs. That story has changed dramatically. Just last month, the FDA approved daraxonrasib, a drug that targets the RAS family of proteins, for certain patients with metastatic pancreatic cancer. Another remarkable milestone in our ability to go after cancer biology that not long ago seemed beyond our reach.
That connection, that speed, that ability to flex and learn, is what made a new the V Foundation supported study in Science Advances so interesting to me. Dr. Kathryn O’Donnell-Mendell and team at University of Texas Southwestern Medical Center also study cancers driven by KRAS, but they study lung cancer, and instead of asking how they could attack KRAS itself, they asked a different question. What else does a cancer driven by KRAS need in order to survive and grow?
They focused their attention on a protein called PCDH7 that is found on the surface of many lung cancer cells. Previous work had suggested that high levels of this protein were associated with worse outcomes in patients, and it seemed that PCDH7 helped strengthen some of the signals cancer cells use to keep growing. For this study, Dr. O’Donnell-Mendell and colleagues developed an antibody designed to attach to PCDH7 and block its activity. And the early data were promising: in several laboratory and mouse models of lung cancer, the antibody slowed tumor growth. Awesome start!
But what caught my attention and made me want to share with you was what happened beyond simply slowing the cancer down: the antibody appeared to help the immune system engage with the tumor. In the models they studied, more cancer fighting T cells and natural killer cells entered the tumors after treatment. Bottom line: the team was essentially seeing two potentially useful effects from the same approach. First, they were interfering with signals the cancer was using to grow AND they were also helping the immune system recognize and attack it.
Bottom line: the team was essentially seeing two potentially useful effects from the same approach. First, they were interfering with signals the cancer was using to grow AND they were also helping the immune system recognize and attack it.
And then there’s one more thing: when the team combined their antibody with drugs that target KRAS, the combinations worked better than either treatment alone in their models. They also tested the antibody in lung cancer models that had become resistant to adagrasib, an existing KRAS targeted therapy, and still saw an effect. That observation matters (actually, it’s huge) because resistance remains one of the biggest challenges in cancer treatment. One of the worst parts about cancer is how remarkably good it is at adapting when we block one route, so finding additional weaknesses is so important.
Bottom line for me is this paper is a beautiful example of how cancer research moves forward. A discovery in pancreatic cancer does not stay confined to pancreatic cancer. The lessons we learn about KRAS, resistance and the pathways cancers depend on can send researchers in entirely new directions across many different tumor types. Sometimes the next advance comes from targeting the cancer driver itself. Sometimes it comes from asking what that cancer driver depends on and finding another place to intervene.
There is still a great deal we do not know, and much more work to do before this approach can move toward patients. But that doesn’t make the finding less exciting to me. Instead, it’s a reminder that progress in cancer research is rarely one straight line from discovery to cure. We learn something, we follow it, we find another vulnerability, and that discovery gives us another question to ask.
Over time, those questions become new possibilities for patients.
Find the O’Donnell-Mendell lab at O’Donnell Lab | UT Southwestern, Dallas, Texas.”
Title: Monoclonal antibodies targeting PCDH7 inhibit tumor growth and enhance immune responses in KRAS-mutant non–small cell lung cancer
Authors: Nicole Novaresi, Poorva Ghosh, Shayna Thomas-Jardin, Hui Deng, Xuejun Fan, Zhiqiang Ku, Wei Xiong, Xiaorong Zhou, Jingfei Zhu, Huiyu Li, Mahesh S. Padanad, Bethany Smith, Chul Ahn, John D. Minna, Zhiqiang An, Ningyan Zhang, Kathryn A. O’Donnell
You can also read:
RAS-Mediated Resistance Emerges Across Oncogene-Driven NSCLC
