Anticipating adaptation: understanding and overcoming cancer drug resistance

Despite major advances in cancer therapy – from cytotoxic chemotherapy to highly targeted small molecules, immune-based treatments and precision radiation – drug resistance remains the primary barrier to durable clinical benefit. Resistance arises as tumours and host systems evolve under therapeutic selective pressure, enabling cancer cells to survive despite effective initial treatment.

For many years, physicians and researchers have overcome cancer drug resistance by turning to new therapies, new drugs and new treatment regimens, moving patients from one effective drug to the next until there are no more options. This is unsustainable for many reasons, including the diverse set of associated unwanted side effects and most importantly it leaves patients with nowhere to turn when the effective treatments run dry.

So we need a different approach; one that targets cancer drug resistance directly, enabling effective treatments to work for longer so that patients can benefit from the treatments that best suit their lifestyle.

How cancers form drug resistance

Classical chemotherapy resistance emerges through well-characterised mechanisms, including increased drug efflux, altered drug metabolism, enhanced detoxification of reactive oxygen species and improved DNA damage repair. Tumours treated with platinum agents, alkylators or topoisomerase inhibitors frequently upregulate error-prone DNA repair pathways, enabling damage tolerance rather than accurate repair. Loss of p53 function and increased expression of anti-apoptotic proteins such as BCL-2 and MCL-1 further enable evasion of cell death. Resistance to radiation therapy can follow similar mechanisms of resistance to chemotherapy, through enhanced DNA repair and hypoxia-induced stem-cell feature acquisition that are intrinsically drug tolerant.

Resistance does not always require new mutations.

Targeted therapies such as tyrosine kinase inhibitors (TKIs) introduce distinct evolutionary pressures. While often highly effective initially, resistance commonly arises through secondary mutations in drug-binding domains that preserve oncogenic signalling while preventing inhibitor engagement – as observed with EGFR, BCR-ABL and ALK inhibitors. TKIs can also initiate bypass signalling pathways that restore proliferative capacity independent of the original oncogenic driver. Importantly, resistance does not always require new mutations. Phenotypic plasticity is characterised by overlapping gene expression changes that have long been recognised as epithelial-to-mesenchymal transition, lineage switching, or adoption of stem-like states.

Phenotypic plasticity is characterised by overlapping gene expression changes that have long been recognised as epithelial-to-mesenchymal transition, lineage switching, or adoption of stem-like states.

Hormone-driven cancers demonstrate additional resistance mechanisms. In breast and prostate cancer, mutations or amplification of oestrogen or androgen receptors enable ligand-independent signalling, while cross-talk with growth factor pathways bypasses hormonal control altogether. As immune therapies can be a fundamentally different platform, their resistance mechanism is generally due to the tumour’s innate immune evasion capability through immunosuppression and the general dearth of viable immune cells that may elicit a response. Often these immune features are determined by the primary tumour of origin or even the new tissue site the tumour metastasised to. Across these diverse treatments, resistance reflects a shared principle: cancer cells survive not because they are stronger, but because they can adapt.

Tumour dormancy and persister cells

An underappreciated but critical contributor to therapy resistance across all treatment classes is tumour dormancy – a biological state in which cancer cells persist without active proliferation and limited metastasis, often for years or even decades. While some of these features might seem initially beneficial to patients, dormant tumour cells can be a source of future relapse.

An underappreciated but critical contributor to therapy resistance across all treatment classes is tumour dormancy.

Tumour dormancy can often have stem-like features and immune tolerance. Typically, cellular dormancy is driven by high p38 MAPK and low ERK signalling, potentially due to poor cell adhesion and TGF-β or BMP signalling that enforce cell-cycle arrest. Dormancy intersects tightly with DNA repair and stress response pathways, involving a mechanism in cell death where surrounding cancer cells are nutritionally supported through metabolic rewiring to survive therapeutic assault.

Attempts to restore treatment sensitivity increasingly exploit these dependencies. DNA damage response inhibitors and synthetic lethality strategies can resensitise tumours to chemotherapy or radiation. Yet cancer plasticity can create persister populations are not permanently resistant but are poised to re-enter proliferation once selective pressure is relieved, seeding relapse with diverse progeny.

Cross-cutting mechanisms of resistance

As cancer research matures, it has become clear that the most dangerous resistance mechanisms are cross cutting, transcending any single drug or modality:

• Epigenetic plasticity allows rapid adaptation without permanent genetic change, enabling tumours to ‘sample’ resistant states until a stable solution emerges
• Metabolic reprogramming supports survival under therapeutic stress and fuels resistance to chemotherapy, TKIs and immunotherapy alike
• Lineage plasticity permits tumours to abandon their original identity altogether, as seen in prostate cancer, yet rare in breast cancers, that escape hormonal therapies by adopting neuroendocrine/small-cell phenotypes
• The tumour microenvironment further reinforces resistance through metabolic support, extracellular matrix signalling, hypoxia and immunosuppression.

Together, these mechanisms argue against viewing resistance as a late-stage failure and instead position it as an inevitable evolutionary outcome of therapy.

Strategies to restore treatment sensitivity

Cancer resistance is not a single event – it’s an evolutionary process. Accordingly, the next ‘silver bullet’ will likely be strategies that aim to counter adaptation through rational combination therapies, dynamic treatment schedules and targeting of the persister states, to limit plasticity itself.

In this framework, success may not always mean complete eradication of cancer cells, but rather long-term containment – maintaining tumours in a controlled, non-lethal state by preventing the emergence or reactivation of resistance. Understanding resistance more as a systemic development rather than an isolated incident allows us to reframe cancer control. For example, using conventional therapies to address the bulk tumour, combined with therapies that can address the tumour microenvironment and the other evolving responses to the initial therapy. A few strategies have already been developed to target cancer’s adaptive properties:

Rational combination strategies

Rational combination therapies simultaneously block oncogenic drivers and bypass pathways and DNA repair dependencies, inclusive of some dormancy pathways already mentioned, have been shown to limit or reverse drug-tolerant persister states. For example, targeting the BMP signalling axis has shown promise in reversing hormone resistance of castrate-resistant prostate cancer.

Adaptive dosing strategies

Adaptive dosing schedules that reduce selective pressure can delay clonal dominance and limit stable resistance emergence. This is in opposition to the concept of reaching the maximal tolerated dosing schedule – often the goal of clinical trials testing cancer drugs.

Targeting dormancy and quiescent cells

Targeting tumour dormancy and quiescent cell survival programmes, such as autophagy, stress-response signalling and cell adhesion cues, offers a path to eliminate the reservoirs that seed late relapse. The combination approach blocks essential metabolic pathways that fuel quiescence or leverage immune cells (T cells) to recognise and destroy them, aiming to prevent relapse and metastasis.

Integrating immune-based therapies

Immune-based therapies are no longer separate from other treatment strategies. Several of these emerging strategies include sensitisation through the reduction of exhausted immune cells and, more recently, mechanisms of immune cell expansion ex vivo, as CAR-T therapies expand into helping those with solid tumours. This also includes the selective T-cell expansion in patients themselves. However, as we understand the role of immune cells in treatments designed to target the tumour cells, new combinations applying immune therapy are being considered.

Remodelling the tumour microenvironment

Remodelling the tumour microenvironment can disrupt stromal protection and normalise vasculature, further enhancing therapeutic durability. This is a strategy to transform a tumour’s supportive surroundings into an anti-cancer state, overcoming barriers like dense stroma, poor blood flow and immunosuppression to enhance therapy effectiveness.

From eradication to containment

Together, these approaches and the important candidates we are working on at Kairos Pharma, like ENV105, shift the goal from chasing resistance after it appears to engineering treatment strategies that prolong sensitivity to standard-of-care therapies by disallowing stem-like cell differentiation and tumour dormancy to transform cancer from a recurrent lethal disease into a manageable chronic condition. On the other hand, KROS201expand the number of T cells available to combat tumours when sufficient numbers are unavailable, in what are often termed immune-cold tumours. This way current immune therapies targeting T-cell exhaustion can act more effectively. These are only two examples where recognised mechanisms of therapy resistance can be addressed through strategic combination therapies.

As we continue to make significant strides in the therapies that target cancer, it is important not to lose sight of the similarly vital task of ensuring those therapies remain viable for the longest period possible.