Cancer drug resistance isn’t one problem, it’s many

14 July 2026 • By Bruno Quinney • #Cancer Research

Posted in Cancer Research, Exclusive Content

Tagged Cancer drug targets, Clinical trial, DNA, Kairos Pharma, Prostate cancer, Stem cells, Tumour biology

Neil Bhowmick, Chief Scientific Officer at Kairos Pharma, explores the biology of cancer drug resistance and the opportunities to overcome it.

Despite extraordinary advancements in how we treat cancer, ranging from cytotoxic chemotherapy to precision immunotherapies, one fundamental barrier consistently impedes durable clinical success. That problem is drug resistance. Therapies that demonstrate impressive initial efficacy often lose their effectiveness over time.

The traditional paradigm for managing this has been reactive. Clinicians cycle patients from one effective drug to the next until no options remain, leaving patients vulnerable when the available treatments inevitably run dry. Tumours can evade treatment through changes in the microenvironment, shifts in cellular signalling, and adaptive responses after initial therapy. Yet many strategies still address resistance uniformly, leaving promising therapies underutilised or abandoned too quickly.

This cycle is unsustainable due to cumulative toxicity and development of comorbidities with each therapeutic cycle. As an inevitable evolutionary outcome of therapeutic selective pressure, drug resistance mechanisms need to be understood in order to address them with agents that can extend efficacy of current therapies with limited added toxicity. By targeting cancer drug resistance directly, we can maintain the efficacy of our best treatments for longer, giving patients as much time as possible on the regimens most suited to their disease.

The evolutionary biology of resistance

Resistance emerges from the predictable biological mandate of survival adaptation. Across diverse treatment modalities, cancer cells survive not because they are inherently stronger, but because they are highly adaptable. When a therapy disrupts a disease process, both the tumour and host systems evolve. While it can be understandable that the favourable mutations in tumour cells enable adaptations to therapy, it is more insidious to think that the patients own non-tumour cells can actively support this resistance mechanism. As an example, growth factors secreted from cancer associated stromal cells promote tumour growth and suppression of the immune system contribute to unchecked metastatic progression.

Classical chemotherapy resistance relies on well-documented mechanisms, such as increased drug efflux, altered metabolism, and enhanced error-prone DNA repair. Targeted treatments, like tyrosine kinase inhibitors (TKIs), introduce unique evolutionary pressures. Resistance here often manifests as secondary mutations in drug-binding domains, frequently observed with EGFR or ALK inhibitors, or through bypass signalling pathways that restore the tumour’s proliferative capacity independent of the initial oncogenic driver.

Resistance does not solely rely on stable genetic mutations. Epigenetic plasticity enables tumours to sample different resistant states without permanent genetic changes until a viable survival mechanism emerges. Similarly, lineage plasticity allows cancer cells to completely abandon their original identity to evade targeted therapies, a phenomenon frequently observed in prostate and lung cancers when they adopt neuroendocrine or small cell phenotypes.

Tumour dormancy and cancer stem cells

One of the most critical, yet underappreciated, contributors to cross-cutting therapy resistance is tumour dormancy. Dormancy is a biological state where cancer cells persist without active proliferation for months, years, or even decades. While suspended in this quiescent state, these persister cells can adopt stem-like features and exhibit immune tolerance, establishing a reservoir poised to seed future relapse once therapeutic pressure is relieved.

This dormancy is driven by intricate signalling networks. It is often characterised by high p38 MAPK and low ERK signalling, alongside transforming growth factor-beta (TGF-β) or bone morphogenetic protein (BMP) signalling that enforces cell-cycle arrest. Much like normal stem cells, which naturally resist environmental toxins to survive and repopulate degenerating tissues, these stem-like cancer cells, and their evil twins as some have come to refer to them, leverage this inherent hardiness to survive our most potent oncological drugs.

Shifting the goal from chasing relapse to long-term containment

Understanding resistance as an evolutionary, systemic process completely changes the drug development paradigm. Our objective must shift from merely eradicating bulk tumours to orchestrating long-term containment and prolonged clinical efficacy. This involves rational combination therapies that anticipate adaptation and target persister states to limit cancer plasticity itself.

At Kairos Pharma, the clinical focus has remained on interrupting the biological pathways that drive resistance, aiming to extend the utility of existing standards of care. Central to this is targeting the CD105 protein, a co-receptor for BMP signalling that supports the dedifferentiation and lineage plasticity of tumour cells. CD105 has been identified as a primary driver of resistance across multiple cancer types. In EGFR-driven non-small cell lung cancer (NSCLC), imaging mass cytometry showed that high CD105 expression on the cell surface correlates with significantly lower overall survival for patients on standard of care EGFR-inhibitor, osimertinib.

Preclinical models and single-cell RNA sequencing analyses suggested that resistance to osimertinib may be marked by the emergence of a transient population of cells expressing a tumour dormancy signature, characterised by elevated glycolysis and chromatin condensation. Targeting CD105 with ENV-105 in this context reduces these dormant cell populations, promote chromatin accessibility, support metabolic reprogramming, and restore tumour sensitivity to osimertinib in preclinical models. In these models, combination approaches demonstrated greater tumour growth inhibition than osimertinib alone, supporting ongoing clinical evaluation of this strategy, including a Phase I adaptive trial for lung cancer patients (NCT05401110).

Clinical impact in prostate cancer

The strategy of neutralising resistance biology is highly applicable to metastatic castration-resistant prostate cancer (mCRPC). In this setting, disease progression often occurs despite treatment with androgen deprivation and second-generation androgen receptor inhibitors, leaving patients to face accumulating toxicities from subsequent, temporarily effective options. ENV-105 was designed not to replace standard hormone therapies, but to antagonise the CD105-driven survival signalling that emerges after initial treatment, effectively differentiating stem-like cancer cells to restore their vulnerability to the original drug.

In a predefined interim analysis of our Phase II trial evaluating men with mCRPC who had failed at least one androgen receptor inhibitor, combining ENV-105 with the standard-of-care hormone therapy apalutamide resulted in a median progression-free survival (PFS) of approximately 13.7 months. All evaluable responders remained progression-free for at least four months, with roughly half maintaining this status beyond one year. Seven out of nine evaluable patients also demonstrated reductions in prostate-specific antigen (PSA) levels.

These findings compare exceptionally well against historical benchmarks. Previous reports of similar hormone therapy switching alone support less than six months of progression free survival. Moreover, ENV-105 in combination with the androgen receptor inhibitor, apalutamide, has proven to be well-tolerated, demonstrating no dose-limiting toxicities, unexpected adverse events. Introducing a resistance-modifying antibody without layering on significant new toxicities is vital for integration into the routine care of older mCRPC patients facing multiple comorbidities.

The next frontier

Drug resistance is a universal medical challenge that stretches beyond oncology into infectious diseases, autoimmune disorders, and other chronic conditions. We cannot afford to discard highly effective therapies the moment a disease adapts; our clinical paradigm doesn’t allow for the approval of new candidates that quickly. By recognising resistance as an actionable biological process and incorporating agents that target cancer plasticity and tumour dormancy into rational combination strategies, we can extend the effective duration of our most powerful medicines and give our patients a better and longer chance to continue to live their lives.

Anticipating and overcoming drug resistance represents one of the defining scientific opportunities of the coming decade. Through collaborative, proactive innovation, we can transform cancer from a rapidly recurrent, lethal disease into a steadily manageable chronic condition, offering patients a more durable and hopeful path forward.

About the author

A leading cancer biologist and translational researcher, Dr Neil Bhowmick is President and Chief Scientific Officer at Kairos Pharma . This is in addition to the Mark Goodson Oncology Research Chair and Professor in the Department of Medicine at Cedars-Sinai Medical Center.