Infigratinib (BGJ 398), a Pan-FGFR Inhibitor, Targets P-Glycoprotein and Increases Chemotherapeutic-Induced Mortality of Multidrug-Resistant Tumor Cells

Abstract

The microtubule-targeting agents (MTAs) are well-known chemotherapeutic agents commonly used for therapy of a broad spectrum of human malignancies, exhibiting epithelial origin, including breast, lung, and prostate cancer. Despite the impressive response rates shortly after initiation of MTA-based therapy, the vast majority of human malignancies develop resistance to MTAs due to the different mechanisms. Here, we report that infigratinib (BGJ 398), a potent FGFR1-4 inhibitor, restores sensitivity of a broad spectrum of ABCB1-overexpressing cancer cells to certain chemotherapeutic agents, including paclitaxel (PTX) and doxorubicin (Dox). This was evidenced for the triple-negative breast cancer (TNBC), and gastrointestinal stromal tumor (GIST) cell lines, as well. Indeed, when MDR-overexpressing cancer cells were treated with a combination of BGJ 398 and PTX (or Dox), we observed a significant increase of apoptosis which was evidenced by an increased expression of cleaved forms of PARP, caspase-3, and increased numbers of Annexin V-positive cells, as well. Moreover, BGJ 398 used in combination with PTX significantly decreased the viability and proliferation of the resistant cancer cells. As expected, no apoptosis was found in ABCB1-overexpressing cancer cells treated with PTX, Dox, or BGJ 398 alone. Inhibition of FGFR-signaling by BGJ 398 was evidenced by the decreased expression of phosphorylated (i.e., activated) forms of FGFR and FRS-2, a well-known adaptor protein of FGFR signaling, and downstream signaling molecules (e.g., STAT-1, -3, and S6). In contrast, expression of MDR-related ABC-transporters did not change after BGJ 398 treatment, thereby suggesting an impaired function of MDR-related ABC-transporters. By using the fluorescent-labeled chemotherapeutic agent PTX-Alexa488 (Flutax-2) and doxorubicin, exhibiting an intrinsic fluorescence, we found that BGJ 398 substantially impairs their efflux from MDR-overexpressing TNBC cells. Moreover, the efflux of Calcein AM, a well-known substrate for ABCB1, was also significantly impaired in BGJ 398-treated cancer cells, thereby suggesting the ABCB1 as a novel molecular target for BGJ 398. Of note, PD 173074, a potent FGFR1 and VEGFR2 inhibitor failed to retain chemotherapeutic agents inside ABCB1-overexpressing cells. This was consistent with the inability of PD 173074 to sensitize Tx-R cancer cells to PTX and Dox. Collectively, we show here for the first time that BGJ 398 reverses the sensitivity of MDR-overexpressing cancer cells to certain chemotherapeutic agents due to inhibition of their efflux from cancer cells via ABCB1-mediated mechanism.

Andrographolide reverts multidrug resistance in KBChR 8‐5 cells through AKT signaling pathway

“…Ferulic acid downregulated ABCB1 and AKT expression in resistant KBCh R 8‐5 cell 64 . Enhanced expression of cleaved caspase 3 was observed on treatment with P‐gp targeted drug, infigratinib (BGJ 398), and PTX in MDR cells 65 . Treatment with DOX and simvastatin showed increased expression of cleaved caspase 3 in the gastric cancer cells 51 .…”

“…64 Enhanced expression of cleaved caspase 3 was observed on treatment with P-gp targeted drug, infigratinib (BGJ 398), and PTX in MDR cells. 65 Treatment with DOX and simvastatin showed increased expression of cleaved caspase 3 in the gastric cancer cells. 51 Furthermore, increased expression of caspase 3 and caspase 9…”

Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

“…Targeting CSC subpopulations has been su gested to eliminate tumors and prevent their recurrence. Both ROS and RNS (reactive n trogen species) are expertly managed by CSCs, and they use the TME to their benefi CSCs also have improved DNA repair capability, and the ability to turn off apopto pathways, leading to drug resistance [223,228,232]. As a result, combating CSC drug r sistance by using the proper medications to block both TOPI and TOPII seems logic [233].…”

Pharmacological Strategies for Overcoming Multidrug Resistance to Chemotherapy

“…A tendency for combined or alternating drug therapy methods, e.g., chemotherapy and immunotherapy or hormonal and radiation therapy, was recently noted as a means to avoid MDR. Modern aspects of the battle with MDR to increase the efficacy of antitumor therapy include the search for ferroptosis inductors (e.g., using erastin) as an alternative cell-death mechanism, the search for stabilizers of epigenetic changes and chromatin confirmational changes, inhibitors of the epithelial–mesenchymal transition, and signaling pathway inhibitors [ 13 ].…”

“…For example, nilotinib (Tasigna), a Bcr-Abl inhibitor, was approved for therapy of chronic myelogenous leukemia and inhibits the functioning of transporters ABCB1, ABCG2, and ABCC10 and eliminates drug resistance. Rivoceranib, a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, eliminates ABCB1- and ABCG2-mediated resistance of tumor cells; lapatinib (Tykerb), a dual tyrosine kinase inhibitor (blocks the HER2/neu and EGFR pathways), inhibits P-gp and MRP-proteins; infigratinib (BGJ 398) is an effective chemosensitizer of tumor cells resistant to paclitaxel and doxorubicin, inhibiting P-gp and MRP-proteins of the ABCB1 family [ 13 ].…”