Systems approach to rational combination therapy: PARP inhibitors

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated activity across a broad spectrum of molecular backgrounds and tumor types, with the greatest activity observed in patients with aberrations in the homologous recombination DNA damage repair pathway. Despite remarkable responses in a subset of patients, the response is usually modest and transient due to the almost inevitable emergence of resistance. Tumors develop resistance through rapid adaptation to the effects of PARPi as well as by generation or selection of genomic aberration. Although adaptive responses results in drug resistance, it also induces therapeutic vulnerabilities that could be exploited with rational combination therapies. To fulfill this role, we established the combinatorial adaptive response therapy (CART) platform by performing reverse-phase protein arrays to characterize adaptive responses, and develop rational combination therapies. Our series of studies strongly support the efficacy of this strategy, wherein targeting the emerging adaptive responses to PARPi with MEK/ERK inhibitors, WEE1/ATR inhibition (inhibitors of S-phase and G2 DNA damage checkpoint), and PI3K/AKT/mTOR inhibition, and showed promising anti-tumor activity in various preclinical models. Importantly, this approach has been proven highly efficient, and several combinational therapies developed from the CART platform are being evaluated in ongoing clinical trials (NCT03801369, NCT03586661, NCT03162627, NCT03544125, NCT02659241, NCT02208375, NCT02316834, and NCT03637491).

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

“…For instance, TC1 cells were defined by high levels of replication stress, which can be functionally associated with high MAPK activity (Sheu et al , 2012; Klotz-Noack et al , 2020). Tumors with high TC1 cell content were strongly positive for PARP, an important therapeutic target (Sun et al , 2020). It is of note that the CMS subtyping system developed for bulk tissue CRC transcriptomes (Guinney et al , 2015) could not distinguish the CRC cell types that we identified here on the single cell level, as most epithelial cancer cells were assigned to CMS1 or CMS2 with the exception of goblet-like cells that can adopt CMS3 (Supplementary Fig.…”

Update on the Role of Poly (ADP-Ribose) Polymerase Inhibitors in the DNA Repair-Deficient Pancreatic Cancers: A Narrative Review

“…Based on the excellent response rates in both arms and the higher rate of hematologic toxicity in the triplet arm, the study group concluded that gemcitabine plus cisplatin is an efficacious regimen in metastatic germ line BRCA or PALB2 mutant PDAC and that the addition of veliparib offered no OR benefit and suggested gemcitabine and cisplatin as the standard therapy in this population. 46 Other trials are exploring the combination of PARP inhibitors with nonplatinum agents. For instance, a phase I trial (NCT03337087) is evaluating irinotecan, liposome, fluorouracil, and leucovorin with rucaparib as second-line therapy in nonselected and BRCA1/2 or PALB2 selected metastatic PDAC.…”

“…The results of several studies conducted in ovarian and breast cancer could be extrapolated in the future to help treat metastatic pancreatic cancer patients such as studies evaluating PI3K (NCT01623349, NCT02208375) and VEGFR signaling (NCT02345265), and cell cycle checkpoint protein inhibitors such as WEE1 (NCT02511795). [46][47][48][49] Despite being one of the most common family of oncogenes, RAS genes have been a notoriously fickle and elusive therapeutic target. Importantly, mutations in KRAS are the initial mutational events for most PDACs (95%).…”

“…Based on the excellent response rates in both arms and the higher rate of hematologic toxicity in the triplet arm, the study group concluded that gemcitabine plus cisplatin is an efficacious regimen in metastatic germ line BRCA or PALB2 mutant PDAC and that the addition of veliparib offered no OR benefit and suggested gemcitabine and cisplatin as the standard therapy in this population. 46 …”

“…The results of several studies conducted in ovarian and breast cancer could be extrapolated in the future to help treat metastatic pancreatic cancer patients such as studies evaluating PI3K (NCT01623349, NCT02208375) and VEGFR signaling (NCT02345265), and cell cycle checkpoint protein inhibitors such as WEE1 (NCT02511795). 46–49 …”