Antineoplastic resistance
Marker Drug Major Conditions Clinical Implications
TYMS 5-Fluorouracil Colorectal , stomach , pancreatic cancer High TYMS may show poor response & less toxicity
DPYD 5-Fluorouracil Colorectal , stomach , pancreatic cancer DPD deficiency associated with higher risk of toxicity
UGT1A1 Irinotecan Colorectal cancer Decreased UGT1A1 activity may increase risk of toxicity
CYP2D6 Tamoxifen Breast cancer Patients with deficient CYP2D6 activity are at greater risks of relapse
EGFR Anti-EGFR therapy Colorectal , lung cancer Activation of EGFR pathways enhances tumor growth , progression , & resistance to therapy
KRAS Anti-EGFR therapy Colorectal , lung cancer KRAS mutation is associated with resistance to anti-EGFR therapy
FCGR3A Rituximab Non-Hodgkin 's lymphoma FCRG3A 158Val/Val genotype may be associated with better response
BRCA1 / BRCA2 Platinum Breast , ovarian cancer BRCA1/2 -mutated cancers are more sensitive to DNA damage . Secondary intragenic mutations confer acquired resistance
Genetic markers for drug sensitivity and resistance
Pharmacogenetics play an increasingly important role in antineoplastic treatment . [ 34 ] Rapid sequencing technologies can identify genetic markers for treatment sensitivity and potential resistance . Certain markers are more representative and more likely to be used clinically . [ 34 ] When BRCA1 and BRCA2 are missing , as in 5 percent to 10 percent of all breast cancers , a stalled fork remains destabilized and its newly synthesized DNA is degraded . This genomic instability means the cancer cell is actually more sensitive to DNA-damaging chemotherapy drugs . [ 35 ]
Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance. There are two general causes of antineoplastic therapy failure: Inherent genetic characteristics, giving cancer cells their resistance and acquired resistance after drug exposure, which is rooted in the concept of cancer cell heterogeneity. Characteristics of resistant cells include altered membrane transport, enhanced DNA repair, apoptotic pathway defects, alteration of target molecules, protein and pathway mechanisms, such as enzymatic deactivation. Since cancer is a genetic disease, two genomic events underlie acquired drug resistance: Genome alterations (e.g. gene amplification and deletion) and epigenetic modifications. Cancer cells are constantly using a variety of tools, involving genes, proteins, and altered pathways, to ensure their survival against antineoplastic drugs.