Non-Genetic Mechanisms of Resistance to Targeted Cancer Therapies: From Cellular Plasticity to Novel Therapeutic Strategies

Disease and Health Research: Recent Developments Vol. 3, Prof. Darko Nozic, Editör, BP international, London, ss.175-192, 2026

Targeted anticancer drugs can produce deep initial responses, yet durable control is frequently

limited by residual tumour cells that survive without a pre-existing, fixed resistance mutation.

These drug-tolerant states are generated through reversible chromatin remodelling,

transcriptional reprogramming, epithelial–mesenchymal plasticity, altered lineage identity,

stem-like programmes, extracellular-matrix signalling and metabolic adaptation. Rather than

representing a single phenotype, persistence is a dynamic spectrum that links acute stress

responses to stable genetic resistance. Experimental studies using lineage tracing, single-cell

sequencing, patient-derived models and serial clinical specimens have shown that therapy can

select pre-existing cell states while also inducing new adaptive states. This chapter integrates

primary experimental and clinical evidence across BRAF-, EGFR-, HER2-, androgen-

receptor- and KRAS-directed therapies. Particular emphasis is placed on AXL, integrins,

Hedgehog signalling and the Hippo–YAP/TAZ–TEAD axis as convergent nodes connecting

cell state, the microenvironment and survival. Pharmacological implications include rational

upfront combinations, temporally sequenced therapy, targeting of persister-specific liabilities

such as GPX4 dependence, and interception of adaptive transcription with TEAD or epigenetic

inhibitors. The central conclusion is that non-genetic resistance should be treated as an

evolving, measurable and therapeutically actionable process rather than as a transient prelude

to mutation.