Inhibitor Resistance In Cancer Research Articles

CD44-hyaluronan mediating endocytosis of iron-platinum alloy nanoparticles induces ferroptotic cell death in mesenchymal-state lung cancer cells with tyrosine kinase inhibitor resistance

While tyrosine kinase inhibitor resistance in cancer is a critical issue in the medical field, it is important for clinical testing as well, since it affects the ultimate outcome of cancer therapy. Yet, no effective solutions have been implemented till date. Clinical observations after tyrosine kinase inhibitor treatment reveal that acquired resistance inevitably limits the curative effects of non-small cell lung cancer treatment because of mutations in the epidermal growth factor receptor gene, which are accompanied by epithelial-mesenchymal transition. Here, for the first time, we report that the transmembrane glycoprotein CD44, which is associated with epithelial-mesenchymal transition, chemoresistance, and cancer progression, mediates enhanced endocytosis of iron-platinum alloy nanoparticles (FePt NPs) in the mesenchymal-state gefitinib-resistant (GR+ and M6) cells, via the binding of the CD44 ligand, hyaluronan, to the surface-absorbed hyaluronan-binding protein 2. Upon treatment with FePt NPs, there was higher cellular uptake in mesenchymal-state GR+ and M6 cells, resulting from cell death through ferroptosis and mitochondrial dysfunction, as compared to that observed in the epithelial-state cells. Mechanistically, inactivation of dihydroorotate dehydrogenase elevated the production of mitochondrial lipid peroxidation, and enhanced the cell death in the epithelial-state HCC827 cells, thereby indicating its role in defense against FePt NPs-induced ferroptosis. Furthermore, induction of ferroptosis has been shown to specifically promote the cell death of drug-tolerant “persister” cells and reverse their resistance as well. Therefore, we concluded that FePt NPs preferentially target mesenchymal drug-tolerant “persister” cells and promote ferroptosis, to overcome their resistance. Statement of significanceIn the present study, we identified FePt NPs as an innovative agent for cancer treatment, particularly in mesenchymal-state cells that exhibit TKI resistance. Mesenchymal-state cancer cells showed enhanced uptake of FePt NPs via CD44-HA-mediated endocytosis, accompanied by severe cell death and mitochondrial morphology alterations, in comparison to epithelial-state cells. We further elucidated the mechanism underlying FePt NPs-induced ferroptotic cell death as via a burst of mitochondrial LPO and DHODH protein inactivation. In addition, we found that FePt NPs inhibit tumor growth in TKI-resistant mesenchymal GR+ cell-bearing mice with better efficacy than the ferroptotic inducer RSL3. Our current findings on using FePt NPs to overcome TKI resistance through ferroptosis activation may offer a alternative strategy for improved cancer treatment.

Expression of Concern: Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity.

Expression of Concern: Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity.

Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity.

MAPK targeting in cancer often fails due to MAPK reactivation. MEK inhibitor (MEKi) monotherapy provides limited clinical benefits but may serve as a foundation for combination therapies. Here, we showed that combining a type II RAF inhibitor (RAFi) with an allosteric MEKi durably prevents and overcomes acquired resistance among cancers with KRAS, NRAS, NF1, BRAF non-V600, and BRAF V600 mutations. Tumor cell-intrinsically, type II RAFi plus MEKi sequester MEK in RAF complexes, reduce MEK/MEK dimerization, and uncouple MEK from ERK in acquired-resistant tumor subpopulations. Immunologically, this combination expands memory and activated/exhausted CD8+ T cells, and durable tumor regression elicited by this combination requires CD8+ T cells, which can be reinvigorated by anti-PD-L1 therapy. Whereas MEKi reduces dominant intratumoral T-cell clones, type II RAFi cotreatment reverses this effect and promotes T-cell clonotypic expansion. These findings rationalize the clinical development of type II RAFi plus MEKi and their further combination with PD-1/L1-targeted therapy. SIGNIFICANCE: Type I RAFi + MEKi are indicated only in certain BRAF V600MUT cancers. In contrast, type II RAFi + MEKi are durably active against acquired MEKi resistance across broad cancer indications, which reveals exquisite MAPK addiction. Allosteric modulation of MAPK protein/protein interactions and temporal preservation of intratumoral CD8+ T cells are mechanisms that may be further exploited.This article is highlighted in the In This Issue feature, p. 521.

HDAC5 Loss Impairs RB Repression of Pro-Oncogenic Genes and Confers CDK4/6 Inhibitor Resistance in Cancer.

The tumor-suppressor protein RB acts as a transcription repressor via interaction of its pocket domain with an LXCXE motif in histone deacetylase (HDAC) proteins such as HDAC1. Here, we demonstrate that HDAC5 deficient for the LXCXE motif interacts with both RB-N (via an FXXXV motif) and RB-C segments, and such interactions are diminished by phosphorylation of RB serine-249/threonine-252 and threonine-821. HDAC5 was frequently downregulated or deleted in human cancers such as prostate cancer. Loss of HDAC5 increased histone H3 lysine 27 acetylation (H3K27-ac) and circumvented RB-mediated repression of cell-cycle-related pro-oncogenic genes. HDAC5 loss also conferred resistance to CDK4/6 inhibitors such as palbociclib in prostate and breast cancer cells in vitro and prostate tumors in vivo, but this effect was overcome by the BET-CBP/p300 dual inhibitor NEO2734. Our findings reveal an unknown role of HDAC5 in RB-mediated histone deacetylation and gene repression and define a new mechanism modulating CDK4/6 inhibitor therapeutic sensitivity in cancer cells. SIGNIFICANCE: This study defines a previously uncharacterized role of HDAC5 in tumor suppression and provides a viable strategy to overcome CDK4/6 inhibitor resistance in HDAC5-deficent cancer.

Role of Akt Activation in PARP Inhibitor Resistance in Cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors have recently been introduced in the therapy of several types of cancers not responding to conventional treatments. However, de novo and acquired PARP inhibitor resistance is a significant limiting factor in the clinical therapy, and the underlying mechanisms are not fully understood. Activity of the cytoprotective phosphatidylinositol-3 kinase (PI3K)-Akt pathway is often increased in human cancer that could result from mutation, expressional change, or amplification of upstream growth-related factor signaling elements or elements of the Akt pathway itself. However, PARP-inhibitor-induced activation of the cytoprotective PI3K-Akt pathway is overlooked, although it likely contributes to the development of PARP inhibitor resistance. Here, we briefly summarize the biological role of the PI3K-Akt pathway. Next, we overview the significance of the PARP-Akt interplay in shock, inflammation, cardiac and cerebral reperfusion, and cancer. We also discuss a recently discovered molecular mechanism that explains how PARP inhibition induces Akt activation and may account for apoptosis resistance and mitochondrial protection in oxidative stress and in cancer.

Combined Androgen receptor blockade overcomes the resistance of breast cancer cells to palbociclib.

The dysregulation of cyclin D -Cyclin-dependent kinase 4/6 (CDK4/6)-Rb axis has been implicated in breast cancer progression and the selective CDK4/6 inhibitors have shown effective activity in advanced breast cancer, especially in tumors driven by the estrogen receptor (ER). However, resistance to these small molecular inhibitors has become an inevitable clinical issue after their initial use. Here, we investigated the potential mechanism of resistance by establishing a CDK4/6 inhibitor palbociclib-resistant breast cancer cell line (MCF-7pR). After prolonged exposure to palbociclib, we detected the loss of the ER signaling and an increase in androgen receptor (AR). Moreover, we demonstrated more localization of AR in the cell nucleus of MCF-7pR compared to the parental cell (MCF-7). We also reported that AR could promote the progression of the cell cycle. Blockade of AR signaling could reduce the level of the relative G1-S cyclins, abolish Rb phosphorylation and inhibit the activation of transcriptional programs in S phase. Furthermore, dual inhibition of AR and CDK4/6 could reverse the resistance of palbociclib both in vitro and in vivo. In sum, our studies provide evidence that AR activation promotes cell cycle progression and cell proliferation in CDK4/6 inhibitor resistance, and identify AR inhibition as a putative novel therapeutic strategy to treat CDK4/6 inhibitor resistance in cancer.

Mechanisms of PARP inhibitor resistance in cancer and insights into the DNA damage response

Editorial summaryInhibitors of poly(ADP-ribose) polymerase (PARPi) have entered the clinic for the treatment of patients with cancers that lack homology-directed DNA repair, but drug resistance remains a clinical hurdle. Recent advances in the identification of PARPi resistance mechanisms have yielded a better understanding of DNA end protection and the relevance of endogenous poly(ADP-ribose) glycohydrolase, highlighting new vulnerabilities.

MAPK Reliance via Acquired CDK4/6 Inhibitor Resistance in Cancer.

Purpose: Loss of cell-cycle control is a hallmark of cancer, which can be targeted with agents, including cyclin-dependent kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G1-S cell-cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon.Experimental Design: In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer.Results: This study demonstrates that acquired palbociclib resistance renders cancer cells broadly resistant to CDK4/6 inhibitors. Acquired resistance was associated with aggressive in vitro and in vivo phenotypes, including proliferation, migration, and invasion. Integration of RNA sequencing analysis and phosphoproteomics profiling revealed rewiring of the kinome, with a strong enrichment for enhanced MAPK signaling across all resistance models, which resulted in aggressive in vitro and in vivo phenotypes and prometastatic signaling. However, CDK4/6 inhibitor-resistant models were sensitized to MEK inhibitors, revealing reliance on active MAPK signaling to promote tumor cell growth and invasion.Conclusions: In sum, these studies identify MAPK reliance in acquired CDK4/6 inhibitor resistance that promotes aggressive disease, while nominating MEK inhibition as putative novel therapeutic strategy to treat or prevent CDK4/6 inhibitor resistance in cancer. Clin Cancer Res; 24(17); 4201-14. ©2018 AACR.

DUB3 Promotes BET Inhibitor Resistance and Cancer Progression by Deubiquitinating BRD4

The bromodomain and extra-terminal domain (BET) protein BRD4 is emerging as a promising anticancer therapeutic target. However, resistance to BET inhibitors often occurs, and it has been linked to aberrant degradation of BRD4 protein in cancer. Here, we demonstrate that the deubiquitinase DUB3 binds toBRD4 and promotes its deubiquitination and stabilization. Expression of DUB3 is transcriptionally repressed by the NCOR2-HDAC10 complex. The NCOR2 gene is frequently deleted in castration-resistant prostate cancer patient specimens, and loss of NCOR2 induces elevation of DUB3 and BRD4 proteins in cancer cells. DUB3-proficient prostate cancer cells are resistant to the BET inhibitor JQ1 invitro and in mice, but this effect is diminished by DUB3 inhibitory agents such as CDK4/6 inhibitorin a RB-independent manner. Our findings identify a previously unrecognized mechanism causing BRD4 upregulation and drug resistance, suggesting that DUB3 is a viable therapeutic target to overcome BET inhibitor resistance in cancer.

Targeting Stat3 Abrogates EGFR Inhibitor Resistance in Cancer

EGF receptor (EGFR) is upregulated in most epithelial cancers where signaling through EGFR contributes to cancer cell proliferation and survival. The limited clinical efficacy of EGFR inhibitors suggests that identification of resistance mechanisms may identify new pathways for therapeutic targeting. STAT3 is upregulated in many cancers and activated via both EGFR-dependent and -independent pathways. In the present study, we tested the consequences of STAT3 inhibition in EGFR inhibitor-resistant head and neck squamous cell carcinoma (HNSCC) and bladder cancer models to determine whether STAT3 blockade can enhance responses to EGFR targeting. pSTAT3 expression was assessed in human HNSCC tumors that recurred following cetuximab treatment. Cetuximab-sensitive and -resistant cell lines were treated with a STAT3 decoy to determine EC(50) concentrations and the effects on STAT3 target gene expression by Western blotting. In vivo assays included evaluation of antitumor efficacy of STAT3 decoy in cetuximab-sensitive and -resistant models followed by immunoblotting for STAT3 target protein expression. Targeting STAT3 with a STAT3 decoy reduced cellular viability and the expression of STAT3 target genes in EGFR inhibitor resistance models. The addition of a STAT3 inhibitor to EGFR blocking strategies significantly enhanced antitumor effects in vivo. Biopsies from HNSCC tumors that recurred following cetuximab treatment showed increased STAT3 activation compared with pretreatment biopsies. These results suggest that STAT3 activation contributes to EGFR inhibitor resistance both in HNSCC and bladder cancer where concomitant targeting of STAT3 may represent an effective treatment strategy.

Tumor heterogeneity and strategies to overcome kinase inhibitor resistance in cancer: lessons from melanoma

Tumor heterogeneity and strategies to overcome kinase inhibitor resistance in cancer: lessons from melanoma

Tyrosine kinase inhibitor resistance in cancer: role of ABC multidrug transporters

Recent antitumor drug research has seen the development of a large variety of tyrosine kinase inhibitors (TKIs) with increasing specificity and selectivity. These are highly promising agents for specific inhibition of malignant cell growth and metastasis. However, their therapeutic potential also depends on access to their intracellular targets, which may be significantly affected by certain ABC membrane transporters. It has been recently shown that several human multidrug transporter ABC proteins interact with specific TKIs, and the ABCG2 transporter has an especially high affinity for some of these kinase inhibitors. These results indicate that multidrug resistance protein modulation by TKIs may be an important factor in the treatment of cancer patients; moreover, the extrusion of TKIs by multidrug transporters may result in tumor cell TKI resistance. Interaction with multidrug resistance ABC transporters may also significantly modify the pharmacokinetics and toxicity of TKIs in patients.