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).

Keywords: PARP inhibitor; RPPA; adaptive response; combination therapy.

Conflict of interest statement

Competing Interests

Gordon B. Mills

Scientific advisory board/Consultant: AstraZeneca, Chrysallis Biotechnology, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda,

Stock/Options/Financial: Catena Pharmaceuticals, ImmunoMet, SignalChem, Tarveda

Licensed Technology HRD assay to Myriad Genetics, DSP patents with Nanostring

Sponsored research: Nanostring Center of Excellence, Ionis (Provision of tool compounds only)

© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Figures

Figure 1.. Rational combination therapies development based on adaptive response to PARP inhibitors evaluated by RPPA

(A) Flow chart of CART platform after PARP inhibitors. (B) Ten cell lines were treated as indicated in the flow chart (A), then cell lysates were evaluated by RPPA with 218 antibodies targeting total and phosphorylated proteins and phosphorylation. Heatmap shows the integrated proteins or phosphorylation alterations following both AZD2281, and BMN673 treatment. To display the generalization, proteins amounts in various treatment conditions (2D/3D, time-points, and dosage) were averaged. Protein levels were normalized to each individual control for AZD2281, or BMN673 respectively, and then ordered by the summing median-centered numbers.

Figure 2.. Concurrent MEK inhibition reverses the activated MAPK pathway after PARPi and leads to cell to death.

(A) PARP inhibition induced a marked increase in RAS/mitogen-activated protein kinase (MAPK) pathway activation, (B) Concurrent MEK inhibition reverses the adaptive responses after PARPi and lead cell to death.