seminar presentation chemoresistance - Copy.pptx

Chemoresistancr

1. Presented by: M. Saleem Cancer drug resistance

2. Introduction: Mediators of intrinsic resistance pre exist in cancer cells. Develops during treatment of tumours that are initially sensitive. Caused by mutations arising during the treatment, adaptive responses. Chemoresistance/ Cancer drug resistance is the ability of cancer cells to evade or cope up with the effects of anticancer drugs.

3. Introduction: Fig. General principles of drug resistance.

4. Drug efflux: Several cell membrane proteins cause chemoresistance by promoting drug efflux. Most notably, ABC transporters (particularly MDR1, MRP1 & BCRP) regulate the flux of chemotherapeutic agents. MDR1 overexpression has been associated with chemoresistance in many cancers, such as, kidney ,colon and liver cancers.

5. L ack of drug activation: Conversion of anti metabolites into most active forms does not occur when the relevant cellular enzyme is absent. Capecitabine 5-Flourouracil Thymidine phosphorylase (Inactive) ( Active ) Thymidylate synthase DNA methylation

6. Alterations in drug targets: Drug response and resistance can be affected by alterations in drug target, such as mutations or changes in expression level. Androgen receptor overexpression in prostate cancers reduces the effectiveness of inhibitors because more target molecules must be inhibited to have a therapeutic effect. Cancers are often highly dependent on specific oncogenic mutations in kinases. Gatekeeper residue mutation in EGFR (T790M) also causes drug resistance.

7. DNA damage repair: Many chemotherapeutic drugs induce DNA damage either directly( e.g. platinum-based drugs) or indirectly(topoisomerase inhibitors). DNA damage induced cell cycle arrest is disrupted in some cancers owing to alterations in oncogenes or tumor suppressor genes. Mutations in p53 can disrupt DNA-damage induced cell cycle arrest. Molecularly targeted agents that inhibit components of DNA damage machinery, such as poly(ADP-ribose) polymerase 1 (PARP1) inhibitors have been developed to overcome repair mediated resistance.

8. Activation of prosurvival signalling: ADAM17 results in chemoresistance by generating ligands for prosurvival signalling pathways . EGFR-targeted therapies have been shown to sensitize various tumor types to agents such as 5-FU,paclitaxel and irinotican in vitro and/or in vivo. Fig. Oncogenic signalling pathways.

9. Summary:

10. Thank you