Viewing Treatment Resistance As A Target

A conversation between John Yu, CEO, Kairos Pharma, and Morgan Kohler

Biotechs often focus on creating new drugs or therapies to target diseases with high unmet need. However, especially in cancer treatment, effective therapies oftentimes lose efficacy over time because cancer adapts and becomes resistant to treatment modalities. Kairos Pharma is working under a different hypothesis, focusing on novel combination therapies with existing effective treatments to resensitize resistant cancers and restore the body's ability to fight the cancer effectively. 

We caught up with John Yu, CEO of Kairos Pharma, so he could discuss the shift in traditional thinking and how viewing treatment resistance as a target instead of an undesirable side effect could allow effective treatments to work for longer.

Cancer drug resistance has been described as something that can itself be targeted rather than simply an inevitable consequence of treatment. What does that shift in thinking change about how researchers should approach oncology drug discovery?

Treating drug resistance as a therapeutic target redefines oncology from a reactive approach into a proactive outcome-extending strategy. Traditionally, drug discovery has focused on developing new monotherapies to replace treatments once tumors inevitably develop resistance. This becomes an issue when patients run out of new approved treatments to shift to, especially in conditions where there are few approved modalities to begin with.

In direct contrast, when researchers target the underlying adaptive process of resistance itself, the goal shifts from abandoning effective standard-of-care therapies to restoring and extending their durability. This allows patients to remain on the treatments that work for them for longer periods of time, extending the time they can keep their condition under control.

This approach requires drug discovery teams to evaluate how cancer cells adapt to therapeutic pressure and design molecules that block those adaptive survival pathways. Neutralizing resistance mechanisms directly preserves the clinical value of existing therapies and keeps patients in response for significantly longer periods, according to our latest interim clinical data.

What led Kairos to identify CD105 as a potential central mechanism of resistance, and what evidence convinced you that it was a driver of resistance rather than simply a biomarker associated with it?

Kairos identified CD105 while investigating why highly effective targeted therapies, such as anti-androgens in prostate cancer and EGFR inhibitors in lung cancer, eventually fail. Under therapeutic pressure, tumor cells upregulate CD105, which activates BMP signaling pathways and drives cancer cells into a stem-like, dedifferentiated state, allowing them to reject treatment modalities that it has come to identify as toxic to its well-being.

Stem cells naturally possess robust survival mechanisms to withstand environmental stress, and cancer stem cells utilize these same pathways to survive various cancer treatments, including hormone therapy, immunotherapy, and beyond. The evidence establishing CD105 as an active functional driver came from functional reversal studies.

Blocking CD105 in its development or after it’s already been established with our lead antibody, ENV105, forces these stem-like cancer cells to revert back into treatment-sensitive cells, restoring vulnerability to the original drug and extending standard-of-care treatment viability. That direct functional dependency confirms CD105 is an active driver of treatment escape.

How does developing a resistance-reversing drug change the discovery and development process compared with developing a conventional stand-alone oncology drug?

Developing a resistance-reversing agent fundamentally alters translational strategy, clinical trial design, and commercial positioning. Unlike conventional stand-alone oncology drugs designed for monotherapy cytotoxicity, resistance-reversing agents are evaluated on their ability to resensitize resistant tumors and prolong the activity of frontline regimens working in combination strategy with those already approved medicines.

Preclinical models moving forward should evaluate acquired treatment resistance rather than untreated baseline cells. Clinically, trial designs focus on combination studies in patients who have progressed on standard care, measuring endpoints like prolonged progression-free survival and restored treatment sensitivity. From a development standpoint, this model enhances the utility of existing standard-of-care therapies rather than attempting to displace them, creating a highly complementary clinical pathway and hopefully giving the patients that need it most more standard-of-care options that work for longer periods of time.

How important is understanding the molecular evolution of a tumor during treatment to identifying new drug targets? Should drug discovery increasingly focus on what cancer cells become under therapeutic pressure, rather than only on what they look like before treatment?

Traditional oncology drug discovery relies heavily on baseline diagnostic biopsies, which capture only a static snapshot of an untreated tumor. Once therapeutic pressure is applied, standard treatments eliminate sensitive cell populations while forcing surviving cells to undergo dynamic molecular adaptation. This selective evolution, including changes to the overall tumor microenvironment, fundamentally alters the biological landscape of the tumor long before clinical progression becomes visible on a scan. Consequently, targets identified at baseline often lose relevance as the surviving cancer cells shift their underlying survival machinery.

Mapping what cancer cells become under therapeutic pressure reveals the precise mechanisms driving treatment resistance. Under intense selective stress, tumor cells frequently downregulate standard targets and upregulate alternative escape pathways, often reverting to a stem-like state. These acquired traits are typically rather predictable survival responses that create distinct molecular vulnerabilities. Focusing on these therapeutic adaptations allows researchers to identify targets that are uniquely exposed only after frontline therapy has begun.

Shifting the discovery paradigm toward tumor evolution enables the development of rational, proactive combination therapies. Instead of waiting for full clinical relapse to switch to an entirely new line of treatment, drug developers can design therapies that hit specific adaptation pathways as they emerge. This approach transforms resistance from an unavoidable dead end into an actionable biological target and allows us to shift from just finding therapies that work to therapies that actually keep our patients healthy for longer. Anticipating tumor adaptation allows clinicians to convert drug resistance back into treatment sensitivity and extend patient responses.

What role do biomarkers play in your resistance strategy? Could measuring CD105 or another molecular feature eventually allow physicians to identify patients whose tumors are most likely to benefit from a resistance-reversing combination?

Biomarkers are essential for precision intervention in drug resistance strategies. Rather than treating all progressing patients broadly, diagnostic tools enable clinicians to identify the precise molecular driver active in any given tumor.

Kairos Pharma has developed a companion biomarker panel designed to measure CD105 expression and associated signaling genes. This diagnostic approach allows physicians to identify patients whose tumors are actively transitioning into a CD105-driven resistant state. By selecting candidates based on verified expression profiles before or during progression, clinical trials can target the patient population most likely to benefit from an ENV105 combination, optimizing clinical efficacy and ensuring targeted patient delivery.

The end goal is to have multiple resistance-targeting mechanisms, such as ENV105, that have proved to be both safe and efficacious in combination with frontline therapies. This would allow clinicians to identify the exact resistance mechanism at play in their patient and choose the proper resensitizing agent accordingly.

Your pipeline also includes approaches aimed at reversing cancer-induced immune suppression, including KROS101 and the T-cell therapy KROS201. Is there a common scientific principle connecting immune suppression and drug resistance in your discovery strategy?

The unifying biological principle across our pipeline is dismantling the adaptive survival defenses that tumors erect under stress. Whether a tumor escapes targeted therapy by transforming into a stem-like state via CD105 or evades the immune system by recruiting regulatory T cells and silencing effector T cells, both outcomes stem from cellular adaptation.

KROS101 addresses immune suppression by expanding killer effector T cells while suppressing regulatory T cells, converting an immunosuppressive tumor microenvironment into an active immune response. KROS201 targets cancer stem cells directly using activated T cells.

Across both targeted resistance and immunotherapy platforms, our strategy targets the specific adaptive mechanisms cancer uses to evade destruction.

What do you think the oncology field gets wrong about combination therapy today? Are there opportunities to systematically discover combinations based on mechanisms of resistance rather than testing combinations largely through empirical trial and error?

The oncology field frequently designs combination therapies empirically, pairing agents simply because each shows single-agent activity or because stacking toxicities seems intuitive. This trial-and-error methodology often results in added toxicity without meaningful synergistic benefit.

The greater opportunity lies in mechanistic combination design built around synthetic lethality and resistance pathways. When a primary therapy blocks a key driver, it forces the tumor to rely on a secondary survival pathway to stay alive. Identifying and targeting that secondary survival pathway creates a rational, highly synergistic combination where neither drug can achieve maximum durability without the other.

Systematically mapping these escape routes allows drug developers to design combinations that prevent resistance before it establishes itself. We have already had incredible breakthrough therapies receive approval in things like metastatic castration-resistant prostate cancer and EGFR-mutated non-small cell lung cancer, but now the concern is patients only see efficacy for a limited window of time. That is where we should be focused: making those therapies work longer.

About The Expert

John Yu, MD, CEO of Kairos Pharma, is a globally respected neurosurgeon and immunotherapy innovator. He is also a professor of neurosurgery and director of surgical neuro-oncology at Cedars-Sinai Medical Center. He holds a BS from Stanford and an MD from Harvard Medical School and MIT. He completed his neurosurgery residency at Massachusetts General Hospital/Harvard and completed an immunology fellowship at the Institut Pasteur in Paris. He has developed eight FDA investigational drugs, holds numerous patents for immunotherapies and nanotechnologies from his NIH-funded laboratory, and has led multiple clinical trials. Prior to Kairos, he served as CEO and chairman of AcTcell and as director of Enviro Therapeutics.