Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function

Steen, Nele Van Der; Keller, KM; Dekker, Henk; Porcelli, Letizia; Honeywell, Richard J.; Meerloo, Johan van; Musters, René J. P.; Kathmann, Ietje; Frampton, Adam E.; Liu, Daniel; Ruijtenbeek, Rob; Rolfo, Christian; Pauwels, Patrick; Giovannetti, Elisa; Peters, Godefridus J.

doi:10.1002/jcp.29463

Cited by 8 publications

(4 citation statements)

References 61 publications

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“…Afatinib and erlotinib show a fair degree of clinical efficacy, which can possibly be explained by the location of the target receptor for these drugs at the membrane (EGFR). The high accumulation of crizotinib and sunitinib is related to the phenomenon of lysosomal accumulation [ 2 , 45 ], which was also observed in other types of cells, such as NSCLC [ 49 ], breast cancer, and gliomas ( Figure S2 ).…”

Section: Discussionmentioning

confidence: 94%

Epithelial Transfer of the Tyrosine Kinase Inhibitors Erlotinib, Gefitinib, Afatinib, Crizotinib, Sorafenib, Sunitinib, and Dasatinib: Implications for Clinical Resistance

Honeywell

Kathmann

Giovannetti

et al. 2020

Cancers

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Background: tyrosine kinase inhibitors (TKIs) inhibit phosphorylation of signaling proteins. TKIs often show large variations in the clinic due to poor pharmacology, possibly leading to resistance. We compared gut absorption of inhibitors of epidermal growth factor receptor (erlotinib, gefitinib, and afatinib), ALK-cMET (crizotinib), PDGFR/BCR-Abl (dasatinib), and multikinase inhibitors (sunitinib and sorafenib). In clinical samples, we measured the disposition of each compound within various blood compartments. Methods: we used an optimized CaCo2 gut epithelial model to characterize 20 µM TKI absorption. The apical/basolateral transfer is considered to represent the gut/blood transfer. Drugs were measured using LC-MS/MS. Results: sorafenib and sunitinib showed the highest apical/basolateral transfer (Papp 14.1 and 7.7 × 10−6 cm/s, respectively), followed by dasatinib (3.4), afatinib (1.5), gefitinib (0.38), erlotinib (0.13), and crizotinib (n.d.). However, the net absorptions for dasatinib, afatinib, crizotinib, and erlotinib were highly negative (efflux ratios >5) or neutral/negative, sorafenib (0.86), gefitinib (1.0), and sunitinib (1.6). A high negative absorption may result in resistance because of a poor exposure of tissues to the drug. Accumulation of the TKIs at the end of the transfer period (A->B) was not detectable for erlotinib, very low for afatinib 0.45 pmol/μg protein), followed by gefitinib (0.79), dasatinib (1.1), sorafenib (1.65), and crizotinib (2.11), being highest for sunitinib (11.9). A similar pattern was found for accumulation of these drugs in other colon cell lines, WiDr and HT29. In clinical samples, drugs accumulated consistently in red blood cells; blood to plasma ratios were all >3 (sorafenib) or over 30 for erlotinib. Conclusions: TKIs are consistently poorly absorbed, but accumulation in red blood cells seems to compensate for this.

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Section: Discussionmentioning

confidence: 94%

Epithelial Transfer of the Tyrosine Kinase Inhibitors Erlotinib, Gefitinib, Afatinib, Crizotinib, Sorafenib, Sunitinib, and Dasatinib: Implications for Clinical Resistance

Honeywell

Kathmann

Giovannetti

et al. 2020

Cancers

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“…A PamChip array comprising 144 kinase peptide substrates was employed to assess the alteration in tyrosine kinase activity upon the application of 10l compound. This study was conducted using SUIT-2 and PDAC-3 cells in biological triplicates, involving three untreated samples and three samples treated with 10l , as outlined previously [35].…”

Section: Methodsmentioning

confidence: 99%

Exploring the therapeutic potential of a novel series of imidazothiadiazoles targeting focal adhesion kinase (FAK) for pancreatic cancer treatment: Synthesis, mechanistic Insights and promising antitumor and safety profile

Carbone,

Pecoraro,

Scianò

et al. 2024

Preprint

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Focal Adhesion Kinase (FAK) is a non-receptor protein tyrosine kinase that plays a crucial role in various oncogenic processes related to cell adhesion, migration, proliferation, and survival. The strategic targeting of FAK represents a burgeoning approach to address resistant tumors, such as pancreatic ductal adenocarcinoma (PDAC).Herein, we report a new series of twenty imidazo[2,1-b][1,3,4]thiadiazole derivatives assayed for their antiproliferative activity against the National Cancer Institute (NCI-60) panel and a wide panel of PDAC models. Lead compound10lexhibited effective antiproliferative activity against immortalized (SUIT-2, CAPAN-1, PANC-1, PATU-T, BxPC-3), primary (PDAC-3) and gemcitabine-resistant clone (PANC-1-GR) PDAC cells, eliciting IC50values in the low micromolar range (1.04-3.44 µM), associated with a significant reduction in cell-migration and spheroid shrinkagein vitro. High-throughput kinase arrays revealed a significant inhibition of the FAK signalling network, associated to induction of cell cycle arrest in G2/M phase, suppression of tumor cell invasion and apoptosis induction. The low selectivity index/toxicity prompted studies using PDAC mouse xenografts, demonstrating significant inhibition of tumor growth and safety. In conclusion, compound10ldisplayed antitumor activity and safety in bothin vitroandin vivomodels, emerging as a highly promising lead for the development of FAK inhibitors in PDAC.

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“…Crizotinib's lysosomotropism has been described earlier (Honeywell et al, 2018;Van Der Steen et al, 2020).…”

Section: Contribution Of Lysosomal Retention To Sustained Target Inhi...mentioning

confidence: 96%

Differences in Sustained Cellular Effects of MET inhibitors Are Driven by Prolonged Target Engagement and Lysosomal Retention

et al. 2022

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Intracellular distribution of drug compounds is dependent on physicochemical characteristics and may have a significant bearing on the extent of target occupancy and, ultimately, drug efficacy. We assessed differences in the physicochemical profiles of MET inhibitors capmatinib, crizotinib, savolitinib, and tepotinib and their effects on cell viability and MET phosphorylation under steady-state and washout conditions (to mimic an open organic system) in a human lung cancer cell line. To examine the differences of the underlying molecular mechanisms at the receptor level, we investigated the residence time at the kinase domain and the cellular target engagement.We found that the ranking of the drugs for cell viability was different under steady-state and washout conditions, and that under washout conditions, tepotinib displayed the most potent inhibition of phosphorylated MET. Postwashout effects were correlated with the partitioning of the drug into acidic subcellular compartments such as lysosomes, and the tested MET inhibitors were grouped according to their ability to access lysosomes (crizotinib and tepotinib) or not (capmatinib and savolitinib). Reversible lysosomal retention may represent a valuable intracellular storage mechanism for MET inhibitors, enabling prolonged receptor occupancy in dynamic, open physiologic systems, and may act as a local drug reservoir. The use of washout conditions to simulate open systems and investigate intracellular drug distribution is a useful characterization step that deserves further investigation. Significance statementGenerally, determination of potency and receptor occupancy is performed under steady-state conditions. In vivo conditions are more complex due to concentration differences between compartments and equilibrium processes.Experiments under steady-state cannot explore effects such as sustained target inhibition. In our study, we have shown that differences between MET inhibitors are observable by applying washout conditions to in vitro assays. This important finding applies to most compound classes and may inspire readers to re-think their assay designs in the future.

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Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function

Cited by 8 publications

References 61 publications

Epithelial Transfer of the Tyrosine Kinase Inhibitors Erlotinib, Gefitinib, Afatinib, Crizotinib, Sorafenib, Sunitinib, and Dasatinib: Implications for Clinical Resistance

Epithelial Transfer of the Tyrosine Kinase Inhibitors Erlotinib, Gefitinib, Afatinib, Crizotinib, Sorafenib, Sunitinib, and Dasatinib: Implications for Clinical Resistance

Exploring the therapeutic potential of a novel series of imidazothiadiazoles targeting focal adhesion kinase (FAK) for pancreatic cancer treatment: Synthesis, mechanistic Insights and promising antitumor and safety profile

Differences in Sustained Cellular Effects of MET inhibitors Are Driven by Prolonged Target Engagement and Lysosomal Retention

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