Cancer treatment has advanced dramatically in recent decades, with breakthrough drugs offering new hope to patients across multiple tumor types. Yet one of oncology’s most stubborn challenges remains: drug resistance.

Many therapies, from targeted agents to immunotherapies, initially deliver strong results only to lose effectiveness over time as cancer cells adapt and fight back. This persistent problem not only undermines existing treatments but also forces clinicians and patients into a frustrating cycle of diminishing options.

Kairos Pharma, a clinical-stage biotechnology company, is aiming to change that. At the helm is Dr. John Yu, a neurosurgeon at Cedars-Sinai and the company’s co-founder and CEO. Drawing on his experience treating patients with some of the most aggressive cancers, Dr. Yu has made it his mission to unravel the mechanisms of resistance and develop therapies that keep drugs working longer. With investigational candidates like ENV-105, designed to reprogram resistant tumor cells, and novel immunotherapies such as KROS-101, Kairos is targeting cancer’s ability to evade both treatment and the immune system.

In an interview with Drug and Device World, Dr. Yu discusses why drug resistance is such a critical obstacle in oncology, how Kairos’ pipeline is designed to overcome it, and what the future might hold for immuno-oncology. He also reflects on the unique perspective he brings as both a clinician and a researcher, and shares his “moonshot” vision for transforming cancer care.

This interview has been edited for clarity, consistency, and length.

Phalguni Deswal [PD]: Why has drug resistance become such a persistent and dangerous challenge in cancer treatment?

Dr. John Yu [JY]: Drug resistance is unfortunately one of the defining realities of cancer care. Nearly every major therapeutic, whether it’s targeted small molecules, hormone therapies, or checkpoint inhibitors, works well at first but eventually stops being effective. That’s because cancer cells are constantly adapting; they evolve ways to survive despite our best efforts to destroy them. It becomes a kind of arms race between therapy and the tumor.

At Kairos, we have identified one central mechanism that contributes to this resistance: the protein CD105, which drives cancer cells into a more stem-cell-like state. These “cancer stem cells” are incredibly resilient, much like normal stem cells in the body, and they resist radiation, chemotherapy, and other drugs. Our goal is to reverse this process, essentially pushing the cells back into a differentiated state where they once again respond to treatment. If we can extend the window of effectiveness for therapies, cancer could be managed more like a chronic disease, similar to how HIV was transformed from a fatal condition into a long-term illness.

PD: How does your lead therapy, ENV-105, work differently from existing treatments?

JY: ENV-105 is an antibody that targets CD105. Specifically, it blocks the pathway that drives cancer cells to become stem-cell-like, while allowing the beneficial block on tumor-promoting signals to remain. By doing this, ENV-105 makes resistant cancer cells more differentiated and, crucially, more responsive to existing drugs.

We have shown this effect in prostate cancer and non-small cell lung cancer, and we’ve seen promising laboratory data in colon and breast cancers as well. Essentially, ENV-105 isn’t designed to replace current therapies. It’s meant to make them work longer and more effectively, even after resistance sets in.

PD: You’ve mentioned combining your drug with existing therapies. Can you explain how that works in practice?

JY: Absolutely. Take prostate cancer as an example: patients on anti-androgen drugs respond well initially, but resistance inevitably develops. By introducing ENV-105, we’ve seen that resistant tumors can once again respond to anti-androgen therapy. Similarly, in lung cancer, patients on EGFR inhibitors like AstraZeneca’s Tagrisso (osimertinib) often relapse after CD105 levels rise. ENV-105 helps restore sensitivity in these cases as well.

The broader implication is that our approach could be applied across multiple cancers, essentially rejuvenating some of the most important drugs in oncology.

PD: Beyond ENV-105, Kairos is also developing immunotherapies. What excites you most about that space?

JY: Immunotherapy has been revolutionary, but its limitations are clear; response rates remain relatively low, and resistance occurs here too. One of our programs, KROS-101, is designed to expand and sustain T cells, the immune system’s “soldiers” against cancer. By stabilizing a molecule called the GITR ligand, a protein that binds to the GITR (Glucocorticoid-induced tumor necrosis factor receptor-related protein), KROS-101 both boosts cancer-killing T cells and reduces suppressive regulatory T cells.

This dual action could make immunotherapies, including checkpoint inhibitors, much more effective. We are also developing KROS-401, which reprograms macrophages in the tumor microenvironment to be anti-tumor rather than pro-tumor. Together, these strategies aim to strengthen the immune system’s attack at multiple weak points.

PD: How has your experience as a clinician shaped the way you develop therapies?

JY: Immensely. As a neurosurgeon, I see firsthand how devastating resistance can be for patients, especially when a treatment initially works and then fails. Those experiences drive me to dig deeper into the biology of resistance and to think about solutions that are truly patient centered. It’s a full-circle process – what I see in the clinic informs the lab, and what we discover in the lab, I try to push back into the clinic through Kairos.

PD: Looking ahead, what is your “moonshot” vision for Kairos Pharma?

JY: Our immediate focus is on delivering results from our clinical trials. We are running a Phase II trial in prostate cancer, testing whether ENV-105 can restore sensitivity to anti-androgen therapy, and a Phase I trial in non-small cell lung cancer. Early results are encouraging, and we’ll be sharing interim findings soon.

The moonshot is simple but profound: to prove that targeting resistance mechanisms can extend the effectiveness of existing drugs across cancers. If successful, this could fundamentally change how we treat cancer, transforming it into a more manageable, chronic condition and giving patients not just more time, but a better quality of life.