CBIO 9 Resistance, biomarkers, personalised treatment

Resistance, biomarkers, perso treatment Introduction- secondary mutation restores the function of BRCAI/BRCA2, resulting in resistance to PARPI: Scenario 1 BRCAS BRCA fonateration PARP Survival Scenario 2 BRCAL PARP Survival BRCAL/BRCAZ altered Scenario 3 BACAT BRCA PARP Survival MRP BRCA1 BRCAZ PARP Synthetic lethality Scenario 4 Math MASAZ shred and inhibited Secondary mutation BRCALIRCA Scenario 5 BACA BACAZ PARP Resistance to PARP Inhibition Therapy resistance in cancer- resistance can occur via genetic & epigenetic changes in cancer cells/tumour microenvironment (ex increased matrix stiffness in liver cancers) 1) changes within cancer cells 2) CSCS give rise to resistance overcome resistance 3) epigenetic changes >> alternative drug working via mechanisms => design drugs that specifically target this resistance => combination of therapies to target aspects of the tumour => personalised treatment Drug resistance in cancer- -diagnosis (1st) = identifying the problem and giving it a name - prognosis (2nd) = prediction of the course of the disease, treatments and results => poor for patients w/ metastatic cancer: 90% of chemo failure are related to drug resistance - pharamacodynamics (PD) = how a drug affects the organism - pharmacokinetics (PK) = how the organism affects the drug drug absorbed distributed => taken inside the cancer cell (drug influx) + activated to kill cells => drug efflux & metabolised eliminated for patient safety Cancer cell Dr Nsorption FD 11 Distribution Metabolan 11 Cell death limit amount of drug reaching tumour drug activity also limited by >> poor influx/ excessive efflux => drug inactivation/ lack of activation >> alterations in drug target => activation of adaptive prosurvival responses >> lack of cell death due to dysfunctional apoptosis Mechanisms of drug resistance- decreased uptake (influx) => methotrexate (toxic folic analogue): mutation of one/ both folate transporters to enter cells => nucleoside analogues: mutation of specific nucleoside transporters >> cisplatin (chemotherapy): reduction in plasma membrane receptors, transporters & endocytosis - increased drug efflux => P-glycoprotein (Pgp): ATP binding protein pump => pumps foreign substances out of cells. => overexpression associated w/ resistance (doxorubicin, taxanes, vinca alkaloids) >> inhibition of Pgp with verapamil can reverse drug resistance altered drug metabolism to increase detoxification => glutathione (GSH): antioxidant that protects the cells => conjugates to platinum chemo drugs & modif them to substrates for ABC transporters (efflux) drug absorbed distributed => taken inside the cancer cell (drug influx) + activated to kill cells => drug efflux & metabolised eliminated for patient safety Cancer cell Dr Nsorption FD 11 Distribution Metabolan 11 Cell death limit amount of drug reaching tumour drug activity also limited by >> poor influx/ excessive efflux => drug inactivation/ lack of activation >> alterations in drug target => activation of adaptive prosurvival responses >> lack of cell death due to dysfunctional apoptosis Mechanisms of drug resistance- decreased uptake (influx) => methotrexate (toxic folic analogue): mutation of one/ both folate transporters to enter cells => nucleoside analogues: mutation of specific nucleoside transporters >> cisplatin (chemotherapy): reduction in plasma membrane receptors, transporters & endocytosis - increased drug efflux => P-glycoprotein (Pgp): ATP binding protein pump => pumps foreign substances out of cells. => overexpression associated w/ resistance (doxorubicin, taxanes, vinca alkaloids) >> inhibition of Pgp with verapamil can reverse drug resistance altered drug metabolism to increase detoxification => glutathione (GSH): antioxidant that protects the cells => conjugates to platinum chemo drugs & modif them to substrates for ABC transporters (efflux) => enhanced DNA damage repair => activate pro-survival signalling m (NOTCH, nuclear factor-kB) resistance can be due to (but often both c.) => a, somatic mutation (insensitive cells cause relapse (become dominant cells) - develop gradually) => b. cancer stem cells insensitive => persist => relapse due to re-growth of persistent stem cells => higher mutation risk => loss of therapeutic control Presentation Pusi Chemotherapy Relapse Post chemotherapy Relapse chemotherapy dandelion effect: Charm b Chemomotan when cut off at ground levels, appears to be gone BUT the roots remain and the dandelion regrows - CTX doo Chertiseme CSCs divide asymmetrically to generate daughter CSCS and differentiated cancer cells C Epigenetics & drug resistance- high rate of epigenetic changes (= not due to DNA) in cancer cells => diversity in gene expression => can lead to drug resistance - heterogenous tumours => drug kills most cells > epigenetically poised persistent tumour sustaining cell (cells in which chromatin domains have > activation-associated histone modif H3K4me3 & repression-associated modif H3K27me3) => resist & survive => expand & lead to treatment tolerance can be rapidly activated upon suitable stimuli 1) chromatin modif conferring tolerance is lost => reversed tolerance (chemo-sensitive relapse) 2) selection of epigenetic state & fix gene expression => resistance (chemo-resistant relapse) 1) (include CSCs) thenortant 2)