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

Single strand breaks

• Nucleotide excision repair
• Base excision repair
• PARP1

DNA DAMAGE Cell death

Environmental factors

(UV, radiation, chemicals)

Normal physiology

(DNA replication, ROS)

MAJOR DNA REPAIR PATHWAYS

Chemotherapy

(alkylating agents, antimetabolites)

Radiotherapy

Helleday T, et al. Nat Rev Cancer. 2008;8:193-204. O’Shaughnessy J, et al. J Clin Oncol 2010

Double strand breaks

• Nonhomologous end-joining
• Homologous recombination

– BRCA1/BRCA2

• Fanconi anemia pathway
• Endonuclease-mediated repair

Replication lesions

• Base excision repair

– PARP1

DNA adducts/base damage

• Alkyltransferases
• Nucleotide excision repair
• Base excision repair

– PARP1

Single Strand Damage : PARP

Ward, Can Treat Reviews 2015

Double Strand Damage

DNA Damage HR mediated-repair

BRCA1 BRIT1 ATM Unknown factors Rad51 RPA Others factors

Survival DSB SSB PARP mediated repair

BRCA2 PARP Others factors

Normal Cells

DNA Damage HR mediated-repair

BRCA1 Unknown factors Rad51 RPA Others factors

Death DSB SSB PARP mediated repair

BRIT1 ATM PARP Others factors

HR-deficient Cancer Cells x x

BRCA1 BRCA2

PARPi MOA: Synthetic Lethality

PARP inhibitors

x x

PARP inhibitors

x x

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

pS6 CHK1 pCHK2 etc.

PARPi PLUS CDKi PI3Ki mTORC1/2i Treat with drug (ie PARPi) Assess effect on protein Predict Rational Therapy

Rational Strategy for Combination Therapy

CART: Combinatorial Adaptive Resistance Therapy Platform

S C D 1 E R − a l p h a _ p S 1 1 8 p 2 7 B i m A R T r a n s g l u t a m i n a s e B e c l i n B a k Y B − 1 P M S 2 G 6 P D M D M 2 _ p S 1 6 6 A T M _ p S 1 9 8 1 p 3 8 a l p h a M A P K E T S − 1 c − K i t Y B − 1 _ p S 1 2 S T A T 5 − a l p h a T I G A R P A l − 1 p 9 R S K p 5 3 G S K 3 − a l p h a − b e t a P K C − p a n _ B e t a I I _ p S 6 6 A n n e x i n _ V I I C h k 1 _ p S 3 4 5 B a x s p a s e − 7 _ c l e a v e d D 1 9 8 A n n e x i n _ I B a d _ p S 1 1 2 S 6 _ p S 2 4 _ S 2 4 4 C h k 1 C h k 2 _ p T 6 8 C D K 1 S 6 _ p S 2 3 5 _ S 2 3 6 F

• x

M 1 R b _ p S 8 7 _ S 8 1 1 C y c l i n _ B 1

I G R O V 1 − A Z D 2 2 8 1 I G R O V 1 − B M N 6 7 3 T O V 2 1 G − A Z D 2 2 8 1 T O V 2 1 G − B M N 6 7 3 S K B r 3 − A Z D 2 2 8 1 B T 4 7 4 − A Z D 2 2 8 1 H C C 1 9 5 4 − A Z D 2 2 8 1 S K O V 3 − A Z D 2 2 8 1 K L E − B M N 6 7 3 H C C 1 9 5 4 − B M N 6 7 3 S K B r 3 − B M N 6 7 3 S K O V 3 − B M N 6 7 3 K L E − A Z D 2 2 8 1 M D A − M B − 4 6 8 − B M N 6 7 3 M D A − M B − 4 6 8 − A Z D 2 2 8 1 B T 4 7 4 − B M N 6 7 3 H C C 1 9 3 7 − A Z D 2 2 8 1 H C C 1 9 3 7 − B M N 6 7 3 E T N 1 − A Z D 2 2 8 1 E T N 1 − B M N 6 7 3

Cyclin B1

R

• w

Z − S c

• r

e

C

• u

n t

pRB FoxM1 pS6 CDK1 pCHK2 CHK1 pS6 SCD1 pER p27 Bim AR pCHK1 pATM pBAD

** ** ** ** ** **

CART: PARP Inhibitor Monotherapy

CHK, PI3K up-regulated

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) Rucaparib (CO-338)

• PI3Ki induce

DNA damage

• PI3Ki increase

PARP levels

• PARPi induce

PI3K pathway

Juvekar Cancer Disc 2012; Ibrahim Cancer Disc 2013

PI3K pathway activity predicts resistance to PARP in vitro

pAKT (S473) rho= 0.81 p= 0.022 pAKT (T308) rho= 0.905 p= 0.005 PI3K Score rho= 0.548 p= 0.171

Cardnell CCR 2013

PI3Ki and PARPi

Juvekar Ca Discovery 2012

Window of Opportunity

Use of Novel Clinical Trial Designs

PARPi

PARPi New Agent

Randomized Discontinuation

Use of Novel Clinical Trial Designs

PARP inhibitor (BIOPSY) Eval at 8 weeks Stable Disease (BIOPSY) R PARPi + New Agent Progressive Disease (BIOPSY)

Summary

• As our use of PARP inhibitors increases, so will
• ur experience with resistance
• Novel trial designs and combinations are

essential to guide patient management

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

Acknowledgements

Thank you

@ShannonWestin