Table 1 Mechanisms of resistance to common cytotoxic chemotherapies and precision medicines
Systemic agent | Target | Resistance mechanism |
|---|---|---|
Platinum-based chemotherapy | DNA | Decreased mismatch repair proficiency (e.g.↓MLH1 & ↓MSH2) |
• cisplatin | ||
• carboplatin | Increased efficiency of other modes of DNA repair (e.g. nucleotide excision repair – ↑EERCC1, trans lesion synthesis - ↑EPOLH, homologous recombination - BRCA1/2 restoration) | |
• oxaliplatin | ||
Microtubule-targeting chemotherapy | Tubulin | Drug efflux via increased expression of MDR-1 |
Changes in microtubule structure (e.g. mutations in β-tubulin and overexpression of βIII-tubulin | ||
• docetaxel | ||
• vinorelbine | ||
Chromosomal instability | ||
EGFR TKi | EGFR TK domain | Resistance mutation, e.g. T790M |
• erlotinib | ||
MET amplification | ||
• gefitinib | ||
EGFR amplification | ||
Transformation to small cell lung cancer | ||
EGFR monoclonal antibody | EGFR extracellular domain | Acquired KRAS or NRAS mutation |
Activation of PIK3CA/PTEN pathway | ||
• cetuximab | ||
• panitumumab | ||
Inhibition of cetuximab binding, e.g. EGFR-S492R | ||
BRAF TKi | BRAF-V600E | Elevated BRAF/CRAF/COT1 expression |
• vemurafenib | ||
• dabrafenib | Acquired mutation in other elements of the MAPK pathway | |
Persistent activation of other kinases, e.g. EGFR and PDGFRβ | ||
ALK TKi | EML4-ALK | Secondary EML4-ALK mutations or rearrangements |
• crizotinib | CD74-ROS1 rearrangement | |
• ceritinib |