Taking on the challenge of cancer drug resistance

Taking on the challenge of cancer drug resistance

Tumour survival, growth, and proliferation demand complex and broad biological capabilities, including proliferative signalling, evasion of growth suppressors, promotion of local blood vessel formation, resistance to cell death, replicative immortality, invasion and metastasis, reprogramming of energy metabolism, and evasion of immune destruction. Tumours are morphologically and phenotypically heterogenous and genetically unstable, exhibiting acquired mutation, gene translocation, and differences in copy number.

Inherent plasticity and adaptability allow tumours to muster multiple mechanisms, which can act independently or in concert to thwart the actions of cytotoxic, anti-metabolic, or molecularly targeted chemotherapy. Primary or innate resistance may involve: mutation; genetic heterogeneity, giving rise to subpopulations of intrinsically resistant cells, such as cancer stem cells; or through drug inactivation or detoxification by enzyme action. Acquired or secondary resistance results from an alteration in drug targets through mutation, changes in target expression, activation of non-target oncogenes, metabolic change, increased transport of the drug out of the cell, and alteration of signalling pathways through epigenetic change.

Promising strategies to overcome resistance

Combination therapy can reduce the probability of resistance by simultaneously targeting different tumour vulnerabilities. Early detection and judicious treatment choice have dramatically improved survival rates for some cancers, but resistance is estimated to contribute to 90% of treatment failures in those with advanced disease. The impact of adaptive or intermittent chemotherapy on the emergence of acquired resistance remains to be established.


• Read the full article in pharmaphorum's Deep Dive digital magazine

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7 August, 2023