1.Basis of resistance 2.Mechanisms of resistance 3.How to overcome resistance. 13/10/2017 Sara Redaelli
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1 Dott.ssa Sara Redaelli 13/10/2017
2 1.Basis of resistance 2.Mechanisms of resistance 3.How to overcome resistance
3 Tumor Heterogeneity: Oncogenic Drivers in NSCLC
4 The Promise of Genotype-Directed Therapy EGFR mutation Erlotinib or gefitinib ALK (or ROS) Crizotinib, other ALK TKIs NSCLC Treatment C Treatment D
5 Marked Activity of Crizotinib in ALK+ NSCLC Update of the Phase 1 Study ORR = 60.8%* in 143 evaluable patients (133 evaluable patients shown) Median response duration = 49.1 wks Median PFS = 9.7 mos *Higher ORR in Asians vs non-asians -30 Camidge et al., Lancet Onc, in press
6 Clonal evolution in cancer: Darwin evolution
7 Clonal evolution in cancer: Darwin evolution
8 Resistance: Primary vs Acquired
9 Resistance: Primary vs Acquired Lack of efficacy to TKI from the start of therapy Arises upon the initial response to TKI lasting for a period of time of variable length
10 1.Basis of resistance 2.Mechanisms of resistance 3.How to overcome resistance
11 TKI Resistance Primary Pharmacokinetics Multi-drug resistance Rapid adaptive response Genetic refractoriness Acquired Target mutation Binding Conformation Target amplification By-pass pathways Adaptive response
12 Primary Resistance: Pharmacokinetics
13 Primary Resistance: Multi-drug resistance P-GLYCOPROTEIN MRP1 BCRP - Polymorphisms - Alteration in expression levels
14 Multi-drug resistance: Pgp overexpression leads to resistance in BcrAbl cells
15 TKI Resistance Primary Pharmacokinetics Multi-drug resistance Genetic refractoriness Rapid adaptive response Acquired Target mutation Binding Conformation Target amplification By-pass pathways Adaptive response
16 Rapid adaptation: BRAF-mutant melanoma vs colon cancer Ras IGF1R EGFR Raf Braf-V600E MEK MEK AKT ERK ERK PROLIFERATION CELL PROLIFERATION DEATH PROLIFERATION
17 TKI Resistance Primary Pharmacokinetics Multi-drug resistance Rapid adaptive response Genetic refractoriness Acquired Target mutation Binding Conformation Target amplification By-pass pathways Adaptive response
18 Target Amplification
19 Target Amplification: BCR/ABL amplified-cml resist to Imatinib BCR ABL BCR ABL Lama S Lama R LeCoutre et al., BLOOD 2000
20 Mean normalized expression Target Amplification: EML4/ALK amplified-nsclc resist to crizotinib ALK EML4 ALK Katayama, PNAS 2010 ALK Target Amplification: NPM/ALK-amplified ALCL resist to brigatinib ALK NPM ALK ALK Ceccon et al., Mol Can Res 2015
21 TKI Resistance Primary Pharmacokinetics Multi-drug resistance Rapid adaptive response Genetic refractoriness Acquired Target mutation Binding Conformation Target amplification By-pass pathways Adaptive response
22 Acquired Resistance: Target mutation
23 Target mutation: BCR/ABL in Chronic Myeloid Leukemia (CML) Mutations in the kinase domain of Abl are the most frequent cause of resistance to TKI treatment Mutations confer resistance trough different mechanisms: Direct alteration of the protein-drug binding Alteration of the protein conformation
24 Target mutation: BCR/ABL in Chronic Myeloid Leukemia (CML) Where mutations occur Structure of Abl in complex with Imatinib
25 Target mutation: BCR/ABL in Chronic Myeloid Leukemia (CML) Mutations in the Imatinib binding site
26 Target mutation: BCR/ABL in Chronic Myeloid Leukemia (CML) The Gatekeeper mutant T315I Thr315 Inhibitor P- loop Ile 315 Inhibitor P- loop 06/10/2016 Sara Redaelli 26
27 Target mutation: BCR/ABL in Chronic Myeloid Leukemia (CML) Mutations altering the protein conformation cannot bind Inactive conformation - Activation loop closed Active conformation - Activation loop open
28 Target mutation: BCR/ABL in Chronic Myeloid Leukemia (CML) Mutations altering the protein conformation P-loop mutations Activation-loop mutations
29 Target mutation: BCR/ABL in Chronic Myeloid Leukemia (CML)
30 tumor evolution Drug 1 E255V
31 Target mutation: ALK mutations conferring crizotinib-resistance
32 Target mutation: ALK mutations conferring crizotinib-resistance C1156Y L1196M
33 Target mutation: EGFR mutations resistant to erlotinib T790M
34 Target mutation: RAS/RAF/MAPK pathway Ras Raf Braf-V600E MEK MEK ERK ERK PROLIFERATION CELL PROLIFERATION DEATH
35 Target mutation: BRAF splice variant resistant to vemurafenib
36 TKI Resistance Primary Pharmacokinetics Multi-drug resistance Rapid adaptive response Genetic refractoriness Acquired Target mutation Binding Conformation Target amplification By-pass pathways Adaptive response
37 By-pass Pathways Survival and proliferation
38 By-pass pathways: RAS-RAF-MAPK pathway in BRAF-mutant cancer cells
39 TKI Resistance Primary Pharmacokinetics Multi-drug resistance Rapid adaptive response Genetic refractoriness Acquired Target mutation Binding Conformation Target amplification By-pass pathways Adaptive response
40 Adaptive response: EGFR activation EGFR Mediates Responses to Small-Molecule Drugs Targeting Oncogenic Fusion Kinases,Cancer Res, 2017
41 1.Basis of resistance 2.Mechanisms of resistance 3.How to overcome resistance
42 Any idea?
43 How to overcome resistances? Dose increase? Shift to another TKI Risk of side effects Based on the resistance profile and on clinical status of the patient
44 Alternative TKI: Next generation Bcr/Abl inhibitors in CML Nilotinib Imatinib-related structure 30-fold more potent than imatinib Bosutinib Structurally unrelated to Imatinib fold more potent than imatinib Dasatinib Structurally unrelated to Imatinib 300-fold more potent than Imatinib
45 Definition of a resistance profile for the second generation TKIs 1. Clinically relevant mutations 2. In vitro cellular model pcdna3 Bcr/Abl-wt pcdna3 Bcr/Abl-wt PCR based site directed mutagenesis pcdna3 Bcr/Abl-mut Proliferation assay Ba/F3 murine cell line transfection
46 3. Proliferation assay and IC50 determination IC50: concentration that inhibits the 50% of cell growth
47 IC50 mut IC50 fold increase = IC50 wt
48
49 Drug 1 Drug 2
50 How to overcome resistances? Dose increase? Shift to another TKI Risk of side effects Based on the resistance profile and on clinical status of the patient Drug combination: 1. Increased therapeutic efficacy 2. Reduction of the dose of each drug in order to obtain a certain effect 3. Reduced risk to generate resistant clones
51 Single treatment Combined treatments Hit the same target twice Hit different targets
52 Hit the same target twice: Combined treatment Imatinib + Bosutinib Different off targets Different Abl binding mode Redaelli S et al - Leukemia Jun;24(6):1223-7
53 How to quantitatively measure the power of a combination? Combination index (CI): A quantitative measure of the degree of drug interaction additive effect (CI = 1), (D) synergism (CI < 1), 1 (D) 2 CI or antagonism (CI > 1) [1] (Dx ) 1 (Dx ) 2 D 1 and D 2 are the doses of drugs 1 and 2 that inhibit x% when used in combination (D x ) 1 and (D x ) 2 are the doses of drugs 1 and 2 that inhibit x% when used alone; Imatinib [nm] Example: x= 50% inhibition (IC50) D1= 1 nm D2= 5 nm (D x )1= 10 nm (D 0 x )2= 50 nm Synergism! Bosutinib SKI-606 [nm] CI = = 0.2
54 Hit the same target twice: Combined treatment Imatinib + Bosutinib Bcr-Abl + Cell lines Imatinib sensitive Imatinib resistant Cell lines Ratio Bos:IM Combination Index (CI) ED50 ED75 ED90 Average CI K562 S 1: KCl 22 S 1: Lama 84 S 1: KU812 1: Ba/F3 Bcr-Abl WT Synergism level Very strong synergism Strong synergism Strong synergism Very strong synergism 1: Synergism K562 R 1: Synergism KCl 22 R 1: Lama 84 R 1: Ba/F3 Bcr-Abl Y253F Ba/F3 Bcr-Abl F317L Ba/F3 Bcr-Abl L384M 1: : : Moderate synergism Moderate synergism Slight synergism Slight synergism Moderate synergism
55 Hit the same target twice: Combined treatment Imatinib + Bosutinib Ratio Bos:IM Combination Index (CI) ED50 ED75 ED90 Average CI Synergism level Patient 1 1: Synergism
56 Single treatment Combined treatments Hit the same target twice Hit different targets
57 Hit two different targets: Combined treatment ALK inhibitor + mtor inhibitor mtor inhibitor: Temsirolimus ALK inhibitors: -Crizotinib -Alectinib -Lorlatinib
58 Hit two different targets: In vitro experiments Proliferation assay Selection of resistant cell lines ALK+ Soft agar assay ALK- Redaelli S et al, Oncotarget 2016 Sep 20. doi: /oncotarget.12128
59 Hit two different targets: In vivo experiments K299 Tumor size ~200mm3 Redaelli S et al, Oncotarget 2016 Sep 20. doi: /oncotarget.12128
60
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