TY - JOUR
T1 - Current and future landscape of poly (ADP-ribose) polymerase inhibition resistance
AU - Hinchcliff, Emily
AU - Chelariu-Raicu, Anca
AU - Westin, Shannon N.
N1 - Funding Information:
The current study was funded by NIH 1P50CA217685-01 SPORE in Ovarian Cancer; NIH P30CA016672 MD Anderson Cancer Center Support Grant; NIH T32 Training Grant 5 T32 CA101642 02; GOG Foundation Scholar Investigator Award.
Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.
PY - 2021/2
Y1 - 2021/2
N2 - To highlight relevant strategies to overcome poly(ADP-ribose) polymerase (PARP) inhibitor resistance and present key clinical trials. Recent findings The use of PARP inhibition (PARPi) for frontline maintenance offers substantial clinical benefit in patients with homologous recombination-deficient tumors. However, expanding PARPi from recurrent therapy to frontline maintenance may potentially result in more PARPi resistant tumors earlier in the treatment continuum and data for the use of PARPi after PARPi remain limited. Clinical evidence demonstrates tumors may develop resistance to PARPi through demethylation of the BRCA promoter or BRCA reversion mutations. Multiple clinical trials investigating therapeutic strategies to overcome resistance, such as combinations of PARPi with antiangiogenic drugs, PI3K/AKT/mTOR, or MEK inhibitors have already been reported and more are ongoing. Furthermore, increasing the amount of DNA damage in the tumor using chemotherapy or cell cycle inhibitors such as ATM, ATR/CHK1/WEE1 is also under exploration. Summary There is increasing clinical interest to identify options to enhance PARPi efficacy and overcome adaptive resistance. PARPi represent a class of drugs that have significantly impacted the treatment and maintenance of ovarian cancer; as the use of PARPi increases, better understanding of resistance mechanisms is essential.
AB - To highlight relevant strategies to overcome poly(ADP-ribose) polymerase (PARP) inhibitor resistance and present key clinical trials. Recent findings The use of PARP inhibition (PARPi) for frontline maintenance offers substantial clinical benefit in patients with homologous recombination-deficient tumors. However, expanding PARPi from recurrent therapy to frontline maintenance may potentially result in more PARPi resistant tumors earlier in the treatment continuum and data for the use of PARPi after PARPi remain limited. Clinical evidence demonstrates tumors may develop resistance to PARPi through demethylation of the BRCA promoter or BRCA reversion mutations. Multiple clinical trials investigating therapeutic strategies to overcome resistance, such as combinations of PARPi with antiangiogenic drugs, PI3K/AKT/mTOR, or MEK inhibitors have already been reported and more are ongoing. Furthermore, increasing the amount of DNA damage in the tumor using chemotherapy or cell cycle inhibitors such as ATM, ATR/CHK1/WEE1 is also under exploration. Summary There is increasing clinical interest to identify options to enhance PARPi efficacy and overcome adaptive resistance. PARPi represent a class of drugs that have significantly impacted the treatment and maintenance of ovarian cancer; as the use of PARPi increases, better understanding of resistance mechanisms is essential.
KW - Homologous recombination
KW - Ovarian cancer
KW - Poly(ADP-ribose) polymerase inhibition combinations
KW - Poly(ADPribose) polymerase inhibition resistance
UR - http://www.scopus.com/inward/record.url?scp=85099172801&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099172801&partnerID=8YFLogxK
U2 - 10.1097/GCO.0000000000000678
DO - 10.1097/GCO.0000000000000678
M3 - Review article
C2 - 33315700
AN - SCOPUS:85099172801
SN - 1040-872X
VL - 33
SP - 19
EP - 25
JO - Current Opinion in Obstetrics and Gynecology
JF - Current Opinion in Obstetrics and Gynecology
IS - 1
ER -