Evolutionary dynamics of cancer multidrug resistance in response to olaparib and photodynamic therapy

Baglo, Yan; Sorrin, Aaron J.; Pu, Xiaocong; Liu, Cindy H.; Reader, Jocelyn; Roque, Dana M.; Huang, Huang‐Chiao

doi:10.1016/j.tranon.2021.101198

Cited by 7 publications

(13 citation statements)

References 61 publications

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“…Notably, the fitness advantage of PARPi-resistant cells was critically dependent on the presence of olaparib as PARPi-sensitive cells slowly dominate the co-cultures under drug-free conditions. Our findings are in line with other 2D and 3D co-culture models [46,47] and reflect the "fitness penalty" of drug resistance [48]. This is particularly true as MDR cancer cells require additional energy to maintain and synthesize drug efflux proteins, thus likely "trading-off" non-essential functions, such as proliferation [49].…”

Section: Discussionsupporting

confidence: 88%

Establishment and Molecular Characterization of an In Vitro Model for PARPi-Resistant Ovarian Cancer

Klotz

Schwarz

Dubrovska

et al. 2023

Cancers

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Overcoming PARPi resistance is a high clinical priority. We established and characterized comparative in vitro models of acquired PARPi resistance, derived from either a BRCA1-proficient or BRCA1-deficient isogenic background by long-term exposure to olaparib. While parental cell lines already exhibited a certain level of intrinsic activity of multidrug resistance (MDR) proteins, resulting PARPi-resistant cells from both models further converted toward MDR. In both models, the PARPi-resistant phenotype was shaped by (i) cross-resistance to other PARPis (ii) impaired susceptibility toward the formation of DNA-platinum adducts upon exposure to cisplatin, which could be reverted by the drug efflux inhibitors verapamil or diphenhydramine, and (iii) reduced PARP-trapping activity. However, the signature and activity of ABC-transporter expression and the cross-resistance spectra to other chemotherapeutic drugs considerably diverged between the BRCA1-proficient vs. BRCA1-deficient models. Using dual-fluorescence co-culture experiments, we observed that PARPi-resistant cells had a competitive disadvantage over PARPi-sensitive cells in a drug-free medium. However, they rapidly gained clonal dominance under olaparib selection pressure, which could be mitigated by the MRP1 inhibitor MK-751. Conclusively, we present a well-characterized in vitro model, which could be instrumental in dissecting mechanisms of PARPi resistance from HR-proficient vs. HR-deficient background and in studying clonal dynamics of PARPi-resistant cells in response to experimental drugs, such as novel olaparib-sensitizers.

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Section: Discussionsupporting

confidence: 88%

Establishment and Molecular Characterization of an In Vitro Model for PARPi-Resistant Ovarian Cancer

Klotz

Schwarz

Dubrovska

et al. 2023

Cancers

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“…Tagging cell lines with fluorescent proteins is an elegant method to decipher the specificity of targeted/nontargeted agents in a heterocellular model. 14,17…”

Section: ■ Resultsmentioning

confidence: 99%

“…Several studies have demonstrated the generation of heterotypic in vitro models, consisting of PDAC and other stromal cells, recapitulating the complex cellular heterogeneity observed in these tumors . While such models have been useful in assessing the response to therapy, most of these studies utilize fixed ratios of these cell types, which is often not the case in PDAC patients, where stromal components have been shown to range from 10 to 90% of the total tumor volume. − In the context of this present study, Tanaka et al have reported the generation and characterization of an in vitro PDAC spheroid model with tunable proportion of stromal components, which recapitulates the PDAC pathophysiology. Motivated by these models, we developed a heterotypic PDAC model, comprising PDAC cells (MIA PaCa-2) and pancreatic cancer-associated fibroblasts (PCAFs) with varying ratios and expressing mCherry and EGFP to track cellular responses, for comparing the efficacy of photoimmunotherapy (PIT) and non-targeted Visudyne-photodynamic therapy (PDT).…”

Section: Introductionmentioning

confidence: 84%

Photoimmunotherapy Retains Its Anti-Tumor Efficacy with Increasing Stromal Content in Heterotypic Pancreatic Cancer Spheroids

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by increased levels of desmoplasia that contribute to reduced drug delivery and poor treatment outcomes. In PDAC, the stromal content can account for up to 90% of the total tumor volume. The complex interplay between stromal components, including pancreatic cancer-associated fibroblasts (PCAFs), and PDAC cells in the tumor microenvironment has a significant impact on the prognoses and thus needs to be recapitulated in vitro when evaluating various treatment strategies. This study is a systematic evaluation of photodynamic therapy (PDT) in 3D heterotypic coculture models of PDAC with varying ratios of patient-derived PCAFs that simulate heterogeneous PDAC tumors with increasing stromal content. The efficacy of antibody-targeted PDT (photoimmunotherapy; PIT) using cetuximab (a clinically approved anti-EGFR antibody) photoimmunoconjugates (PICs) of a benzoporphyrin derivative (BPD) is contrasted with that of liposomal BPD (Visudyne), which is currently in clinical trials for PDT of PDAC. We demonstrate that both Visudyne-PDT and PIT were effective in heterotypic PDAC 3D spheroids with a low stromal content. However, as the stromal content increases above 50% in the 3D spheroids, the efficacy of Visudyne-PDT is reduced by up to 10-fold, while PIT retains its efficacy. PIT was found to be 10-, 19-, and 14-fold more phototoxic in spheroids with 50, 75, and 90% PCAFs, respectively, as compared to Visudyne-PDT. This marked difference in efficacy is attributed to the ability of PICs to penetrate and distribute homogeneously within spheroids with a higher stromal content and the mechanistically different modes of action of the two formulations. This study thus demonstrates how the stromal content in PDAC spheroids directly impacts their responsiveness to PDT and proposes PIT to be a highly suited treatment option for desmoplastic tumors with particularly high degrees of stromal content.

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“…PDT involves the light-activation of photosensitive dyes (photosensitizers) resulting in the generation of reactive molecular species which can induce direct cytotoxicity and modulate biological processes [ 10 ]. Prior work has established harmonization between PDT and PARPi as an anti-cancer combination regimen for applications in ovarian, gastric, pancreatic, and skin cancers [ 11 – 14 ]. Tanaka et al found that talaporfin-mediated PDT enhanced PARP-trapping capabilities of olaparib; and their combination significantly suppressed gastric tumor growth in a xenograft murine model [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Lei et al codelivered chlorin e6 and olaparib to pancreatic cancer cells and demonstrated that their combination enhanced cytotoxicity, reactive oxygen species generation, and DNA damage [ 13 ]. We have previously demonstrated that olaparib in combination with PDT using benzoporphyrin derivative (BPD) effectively reduced survival and clonogenicity of a coculture system of chemo-sensitive and chemo-resistant ovarian cancer cells [ 11 ]. In the same study, we further demonstrated that a lipidated photosensitizer formulation reduced selective survival advantage of the chemo-resistant cells, effectively redirecting cancer evolution dynamics [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Co-Packaged PARP inhibitor and photosensitizer for targeted photo-chemotherapy of 3D ovarian cancer spheroids

Sorrin,

Dasgupta,

McNaughton

et al. 2024

Cell Biosci

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Background Within the last decade, poly(ADP-ribose) polymerase inhibitors (PARPi) have emerged in the clinic as an effective treatment for numerous malignancies. Preclinical data have demonstrated powerful combination effects of PARPi paired with photodynamic therapy (PDT), which involves light-activation of specialized dyes (photosensitizers) to stimulate cancer cell death through reactive oxygen species generation. Results In this report, the most potent clinical PARP inhibitor, talazoparib, is loaded into the core of a polymeric nanoparticle (NP-Tal), which is interfaced with antibody-photosensitizer conjugates (photoimmunoconjugates, PICs) to form PIC-NP-Tal. In parallel, a new 3D fluorescent coculture model is developed using the parental OVCAR-8-DsRed2 and the chemo-resistant subline, NCI/ADR-RES-EGFP. This model enables quantification of trends in the evolutionary dynamics of acquired chemoresistance in response to various treatment regimes. Results reveal that at a low dosage (0.01 μM), NP-Tal kills the parental cells while sparing the chemo-resistant subline, thereby driving chemoresistance. Next, PIC-NP-Tal and relevant controls are evaluated in the 3D coculture model at multiple irradiation doses to characterize effects on total spheroid ablation and relative changes in parental and subline cell population dynamics. Total spheroid ablation data shows potent combination effects when PIC and NP-Tal are co-administered, but decreased efficacy with the conjugated formulation (PIC-NP-Tal). Analysis of cell population dynamics reveals that PIC, BPD + NP-Tal, PIC + NP-Tal, and PIC-NP-Tal demonstrate selection pressures towards chemoresistance. Conclusions This study provides key insights into manufacturing parameters for PARPi-loaded nanoparticles, as well as the potential role of PDT-based combination therapies in the context of acquired drug resistance.

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Evolutionary dynamics of cancer multidrug resistance in response to olaparib and photodynamic therapy

Cited by 7 publications

References 61 publications

Establishment and Molecular Characterization of an In Vitro Model for PARPi-Resistant Ovarian Cancer

Establishment and Molecular Characterization of an In Vitro Model for PARPi-Resistant Ovarian Cancer

Photoimmunotherapy Retains Its Anti-Tumor Efficacy with Increasing Stromal Content in Heterotypic Pancreatic Cancer Spheroids

Co-Packaged PARP inhibitor and photosensitizer for targeted photo-chemotherapy of 3D ovarian cancer spheroids

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