Mechanisms of resistance and strategies to restore PARP inhibitor - PowerPoint PPT Presentation

Mechanisms of resistance and strategies to restore PARP inhibitor sensitivity Shannon N. Westin, MD, MPH University of Texas MD Anderson Cancer Center

VERBAL DISCLOSURE • Consultant: AstraZeneca, Medivation, Roche, Ovation, Vermillion • Research Support: AstraZeneca, Critical Outcomes Technologies, Inc., Novartis

Agenda • Mechanisms of PARP inhibitor activity • Mechanisms of PARP inhibitor resistance – Adaptive resistance • Combinations of interest (to be further explored by J. Liu)

Mechanisms of DNA Repair Environmental factors DNA DAMAGE (UV, radiation, chemicals) Normal physiology Cell death (DNA replication, ROS) Chemotherapy (alkylating agents, antimetabolites) Radiotherapy MAJOR DNA REPAIR Replication lesions Single strand breaks PATHWAYS • Base excision repair • Nucleotide excision repair – PARP1 • Base excision repair Double strand breaks DNA adducts/base damage • PARP1  Nonhomologous end-joining • Alkyltransferases  Homologous recombination • Nucleotide excision repair – BRCA1/BRCA2 • Base excision repair  Fanconi anemia pathway – PARP1  Endonuclease-mediated repair Helleday T, et al. Nat Rev Cancer. 2008;8:193-204. O’Shaughnessy J, et al. J Clin Oncol 2010

Single Strand Damage : PARP

Double Strand Damage Ward, Can Treat Reviews 2015

PARPi MOA: Synthetic Lethality Normal Cells HR-deficient Cancer Cells DNA Damage DNA Damage SSB SSB DSB DSB PARP PARP HR HR mediated repair mediated-repair mediated repair mediated-repair PARP PARP x x x inhibitors inhibitors ATM ATM BRCA1 BRCA1 BRCA1 PARP PARP RPA RPA BRIT1 BRIT1 BRCA2 BRCA2 Others Unknown Others Unknown Others factors factors Others factors factors Rad51 Rad51 factors factors x x x Death Survival

Beyond BRCA – Mechanisms of HR deficiency Konstantinopoulos Cancer Discovery 2015

Which of the following molecular aberrations does NOT lead to homologous recombination deficiency? A. BRCA1/2 germline mutation B. CDK12 mutation C. Cyclin E1 amplification D. BRCA1 promotor methylation E. ATM mutation

PARPi: MOA

PARPi: MOA

Which of the following is NOT a potential mechanism of action of PARP inhibitors? A. Synthetic lethality in HR deficient tumors B. DNA cross-linking C. PARP trapping to damaged DNA D. Promotion of non-homologous end joining

Single Agent PARPi Success • Single agent SELECTED – BRCA mutant – Phase II olaparib – 33% – Phase II veliparib – 25% – Phase II rucaparib – 69% • Single agent UNSELECTED – Phase II olaparib – 24% – Phase II rucaparib – 30% in “BRCA-like” Audeh Lancet 2010; Gelmon Lancet Onc 2011 , Coleman Gyn Onc 2015, Swisher SGO 2015,

Mechanisms of Resistance • Intrinsic/Innate • Acquired • Adaptive Ashworth Nat Med 2013

Resistance: Drug Partners (HR) • BRCA reversion mutations – Open reading frame restored = functional protein Sakai, Nature 2008

Induced/Sporadic PARPi Resistance Ashworth, Cancer Res 2008

Resistance: Drug Partners (HR) • 53BP1 loss of function – Balance between BRCA1 and 53BP1 – Decreased 53BP1 = Increase HR and decrease NHEJ Ashworth Nat Med 2013

Resistance: Drug Target (PARPi) • Increased PgP – P-glycoprotein efflux pump – Up-regulation of abcb1a or abcb1b genes Rottenberg PNAS 2008

Resistance: Drug Target (PARPi) • Loss of PARP1 expression – Mutation – Epigenetic silencing Pettitt PLOS One 2013, Liu Mol Can Res 2009

Therapeutic Opportunities • 6-thioguanine in BRCA2 mutant tumors • Chemotherapy in 53BP1 loss of function – Platinum – Doxorubicin • PgP reversal agents – Tariquidar – Verapamil Ang CCR 2013; Rottenberg PNAS 2008; Oplustilova Cell Cycle 2012; Issaeva Can Res 2010

Which of the following agents may reverse PARP inhibitor resistance due to secondary BRCA2 mutations ? A. Cisplatin B. Verapamil C. Doxorubicin D. 6-thioguanine E. Tariquidar

Adaptive Resistance

Rational Strategy for Combination Therapy Predict Treat with drug Rational Therapy (ie PARPi) PARPi PLUS CDKi Assess PI3Ki effect on pS6 mTORC1/2i protein CHK1 pCHK2 etc. CART: Combinatorial Adaptive Resistance Therapy Platform

CART: PARP Inhibitor Monotherapy pCHK2 FoxM1 Color Key p27 and Histogram CDK1 CHK1 pER 0 0 3 pRB Bim pCHK1 n t u pS6 o 0 2 C AR pS6 SCD1 pATM Cyclin B1 pBAD 1 0 CHK, PI3K − 2 0 2 R o w Z − S c o r e E T N 1 − B M N 6 7 3 E T N 1 − A Z D 2 2 8 1 H C C 1 9 3 7 − B M N 6 7 3 up-regulated H C C 1 9 3 7 − A Z D 2 2 8 1 B T 4 7 4 − B M N 6 7 3 ** M D A − M B − 4 6 8 − A Z D 2 2 8 1 ** M D A − M B − 4 6 8 − B M N 6 7 3 ** K L E − A Z D 2 2 8 1 ** S K O V 3 − B M N 6 7 3 S K B r 3 − B M N 6 7 3 H C C 1 9 5 4 − B M N 6 7 3 ** K L E − B M N 6 7 3 ** S K O V 3 − A Z D 2 2 8 1 H C C 1 9 5 4 − A Z D 2 2 8 1 B T 4 7 4 − A Z D 2 2 8 1 S K B r 3 − A Z D 2 2 8 1 T O V 2 1 G − B M N 6 7 3 T O V 2 1 G − A Z D 2 2 8 1 I G R O V 1 − B M N 6 7 3 I G R O V 1 − A Z D 2 2 8 1 m R D K R K 1 8 7 e n k 1 2 6 1 1 2 a 1 3 a 0 5 x 8 2 4 1 8 1 6 M 1 1 1 D S K V _ K B 1 2 A s a − M P 6 8 P − t 0 h A − S 5 6 I 4 a 9 I 1 4 k 6 3 1 C B B B S i G e I B n D 1 p a i c 1 9 A − 1 p A R p t 6 _ 3 1 1 2 h T 2 8 _ S i e l 6 S M S b S S D S S C S x S S n Y G 1 T P n x p C n m B P S c a l − i o E 0 e _ F p p p − l T a p p d p _ _ _ i a I 9 x n 2 _ _ p _ 5 h _ e i _ e _ 0 5 7 i c a h p n l y a 2 M M _ 1 T p n 1 v A d 4 k 3 0 C A h h u p − a I n k a a 2 C 2 8 t B a I B S S S p D T a T A C h e g S l − e l M A l 8 Y B t p p p a s c l 3 l _ _ _ _ − n 3 K _ R 7 6 6 b a p S n R − S S E T G r a e p − s C a p K s P

DNA Repair and Checkpoints • CDKs promote cell cycle arrest: allow for DNA repair – CDK4/6: G1-S – CDK1/2: G2-M • CDKs responsible for phosphorylation of BRCA

Therapeutic Opportunities: CDK • CDK1/2 – dinaciclib • CDK 4/6 – palbocicib, ribociclib, abemaciclib • Pan CDK – roniciclib • ATR/Chk1 – AZD6738 • ATM/Chk2 – KU59403

Therapeutic Opportunities: Anti-angiogenics • PARP inhibition – inhibits angiogenesis • Hypoxic stress – regulates DNA repair pathways – Genomic instability – Mutator phenotype • Chronic hypoxia – development of HRD – Down-regulation of BRCA, RAD51 • Combinations with bevacizumab, cediranib Scanlon DNA Repair 2015; Dean Br J Cancer 2012; Liu Eur J Cancer 2013

Therapeutic Opportunities: PI3Ki Olaparib (AZD2281) • PI3Ki induce DNA damage • PI3Ki increase PARP levels Rucaparib (CO-338) • PARPi induce PI3K pathway Juvekar Cancer Disc 2012; Ibrahim Cancer Disc 2013

PI3K pathway activity predicts resistance to PARP in vitro pAKT (T308) pAKT (S473) PI3K Score rho= 0.905 p= 0.005 rho= 0.81 p= 0.022 rho= 0.548 p= 0.171 Cardnell CCR 2013

PI3Ki and PARPi Juvekar Ca Discovery 2012

Use of Novel Clinical Trial Designs Window of Opportunity PARPi

Use of Novel Clinical Trial Designs Randomized Discontinuation New Agent PARPi Progressive Stable PARP Eval at Disease Disease R inhibitor 8 weeks (BIOPSY) (BIOPSY) (BIOPSY) PARPi + New Agent

Summary • As our use of PARP inhibitors increases, so will our experience with resistance • Novel trial designs and combinations are essential to guide patient management

Acknowledgements • Robert L. Coleman, MD • Gordon B. Mills, MD, PhD • Lew Cantley, PhD • Gerburg Wulf, PhD • Ursula Matulonis, MD • Joyce Liu, MD, PhD

@ShannonWestin Thank you