Table 1 Factors of inter-/intratumoral heterogeneity affecting drug resistance
Key biologic mechanisms | Molecular-phenotypic link to resistance | Drug resistance—intrinsic and acquired |
|---|---|---|
Genetic | Tumor mutational burden | • Mutational heterogeneity and co-occurrence of different driver mutations that confer intrinsic resistance • Activation of bypass and redundant signaling pathway |
Genomic/Epigenomic | Tumor adaptive molecular evolution/reprogramming | • Treatment-induced temporal and spatial driver mutational/non-mutational evolution • Acquired activation of bypass signaling pathways • Adaptively altered transcriptome • Therapy-induced secretome • Adaptively altered metabolome • Adaptive mitochondrial reprogramming |
Proteomic/Neoantigenic | ||
Metabolic/Metabolomic | ||
Tumor microenvironment | TME and host interactions | • Increased availability of resistance-promoting ligand whether intrinsic of the stromal cells or influenced by tumor cell secretions • Heterogeneous development of physical or stromal barriers to drug penetrance • Heterogeneous organ-specific stromal milieu providing different drug-protective mechanisms to tumor cells • Pharmacokinetic failure from differential exposure to therapy |