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Table 1 Factors of inter-/intratumoral heterogeneity affecting drug resistance

From: Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy

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