ABSTRACT
Immune checkpoint blockade has emerged as a potent new tool in the war on cancer. However, only a subset of cancer patients benefit from this therapeutic modality, sparking a search for combination therapies to increase the fraction of responding patients. We argue here that inhibition of protein phosphatase 2A (PP2A) is a promising approach to increase responses to immune checkpoint blockade and other therapies that rely on the presence of tumor-reactive T cells. Inhibition of PP2A increases neoantigen expression on tumor cells, activates the cGAS/STING pathway, suppresses regulatory T cells, and increases cytotoxic T cell activation. In preclinical models, inhibition of PP2A synergizes with immune checkpoint blockade and emerging evidence indicates that patients who have tumors with mutations in PP2A respond better to immune checkpoint blockade. Therefore, inhibition of PP2A activity may be an effective way to sensitize cancer cells to immune checkpoint blockade and cell-based therapies using tumor-reactive T cells.
ABSTRACT
Most targeted cancer drugs inhibit the oncogenic signals to which cancer cells are addicted. We discuss here a counterintuitive approach to cancer therapy, which consists of deliberate overactivation of the oncogenic signals to overload the stress responses of cancer cells. We discuss why such overactivation of oncogenic signaling, combined with perturbation of the stress response pathways, can be potentially effective in killing cancer cells, aiming to inspire further discussion and consideration.
Subject(s)
Neoplasms , Signal Transduction , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/metabolism , Signal Transduction/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Animals , Oncogenes , Molecular Targeted Therapy/methodsABSTRACT
PURPOSE: The development of resistance limits the clinical benefit of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600-mutated melanoma. It has been shown that short-term treatment (14 days) with vorinostat was able to initiate apoptosis of resistant tumor cells. We aimed to assess the antitumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600-mutated melanoma who progressed after initial response to BRAFi/MEKi. PATIENTS AND METHODS: Patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma were treated with vorinostat 360 mg once daily for 14 days followed by BRAFi/MEKi. The primary endpoint was an objective response rate of progressive lesions of at least 30% according to Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included progression-free survival, overall survival, safety, pharmacokinetics of vorinostat, and translational molecular analyses using ctDNA and tumor biopsies. RESULTS: Of the 26 patients with progressive BRAFi/MEKi-resistant BRAFV600-mutated melanoma receiving treatment with vorinostat, 22 patients were evaluable for response. The objective response rate was 9%, with one complete response for 31.2 months and one partial response for 14.9 months. Median progression-free survival and overall survival were 1.4 and 5.4 months, respectively. Common adverse events were fatigue (23%) and nausea (19%). ctDNA analysis showed emerging secondary mutations in NRAS and MEK in eight patients at the time of BRAFi/MEKi resistance. Elimination of these mutations by vorinostat treatment was observed in three patients. CONCLUSIONS: Intermittent treatment with vorinostat in patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma is well tolerated. Although the primary endpoint of this study was not met, durable antitumor responses were observed in a minority of patients (9%).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Histone Deacetylase Inhibitors , Melanoma , Mutation , Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf , Vorinostat , Humans , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Melanoma/mortality , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Vorinostat/administration & dosage , Vorinostat/pharmacology , Female , Male , Middle Aged , Aged , Adult , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylase Inhibitors/adverse effects , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Proof of Concept Study , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/drug effects , Aged, 80 and overABSTRACT
Perturbation of protein phosphorylation represents an attractive approach to cancer treatment. Besides kinase inhibitors, protein phosphatase inhibitors have been shown to have anti-cancer activity. A prime example is the small molecule LB-100, an inhibitor of protein phosphatases 2A/5 (PP2A/PP5), enzymes that affect cellular physiology. LB-100 has proven effective in pre-clinical models in combination with immunotherapy, but the molecular underpinnings of this synergy remain understood poorly. We report here a sensitivity of the mRNA splicing machinery to phosphorylation changes in response to LB-100 in colorectal adenocarcinoma. We observe enrichment for differentially phosphorylated sites within cancer-critical splicing nodes of U2 snRNP, SRSF and hnRNP proteins. Altered phosphorylation endows LB-100-treated colorectal adenocarcinoma cells with differential splicing patterns. In PP2A-inhibited cells, over 1000 events of exon skipping and intron retention affect regulators of genomic integrity. Finally, we show that LB-100-evoked alternative splicing leads to neoantigens that are presented by MHC class 1 at the cell surface. Our findings provide a potential explanation for the pre-clinical and clinical observations that LB-100 sensitizes cancer cells to immune checkpoint blockade.
Subject(s)
Colonic Neoplasms , RNA Splicing , Humans , Alternative Splicing/drug effects , Antigens, Neoplasm/metabolism , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Cell Line, Tumor , Colonic Neoplasms/genetics , Colonic Neoplasms/immunology , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Enzyme Inhibitors/pharmacology , Phosphorylation , Protein Phosphatase 2/metabolism , RNA Splicing/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Serine-Arginine Splicing Factors/metabolism , Serine-Arginine Splicing Factors/genetics , Piperazines/pharmacologyABSTRACT
Drug-tolerant persisters (DTPs) are a rare subpopulation of cells within a tumor that can survive therapy through nongenetic adaptive mechanisms to develop relapse and repopulate the tumor following drug withdrawal. Using a cancer cell line with an engineered suicide switch to kill proliferating cells, we perform both genetic screens and compound screens to identify the inhibition of bromodomain and extraterminal domain (BET) proteins as a selective vulnerability of DTPs. BET inhibitors are especially detrimental to DTPs that have reentered the cell cycle (DTEPs) in a broad spectrum of cancer types. Mechanistically, BET inhibition induces lethal levels of ROS through the suppression of redox-regulating genes highly expressed in DTPs, including GPX2, ALDH3A1, and MGST1. In vivo BET inhibitor treatment delays tumor relapse in both melanoma and lung cancer. Our study suggests that combining standard of care therapy with BET inhibitors to eliminate residual persister cells is a promising therapeutic strategy.
Subject(s)
Lung Neoplasms , Neoplasm Recurrence, Local , Humans , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/geneticsABSTRACT
The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes.
Subject(s)
Neoplasms , Humans , Carcinogenesis , Microbiota , Neoplasms/genetics , Neoplasms/pathology , Neoplasms/therapy , Obesity/complications , Quality of LifeABSTRACT
Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity of such aberrant signaling. Although inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of protein phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor-suppressive resistance. Significance: A therapy consisting of deliberate hyperactivation of oncogenic signaling combined with perturbation of the stress responses that result from this is very effective in animal models of colon cancer. Resistance to this therapy is associated with loss of oncogenic signaling and reduced oncogenic capacity, indicative of tumor-suppressive drug resistance.
Subject(s)
Colonic Neoplasms , Protein Phosphatase 2 , Signal Transduction , Humans , Animals , Protein Phosphatase 2/metabolism , Mice , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Colonic Neoplasms/genetics , Xenograft Model Antitumor Assays , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Drug Resistance, Neoplasm , Nuclear Proteins/metabolism , Nuclear Proteins/genetics , DNA ReplicationABSTRACT
The past decade has witnessed significant advances in the systemic treatment of advanced hepatocellular carcinoma (HCC). Nevertheless, the newly developed treatment strategies have not achieved universal success and HCC patients frequently exhibit therapeutic resistance to these therapies. Precision treatment represents a paradigm shift in cancer treatment in recent years. This approach utilizes the unique molecular characteristics of individual patient to personalize treatment modalities, aiming to maximize therapeutic efficacy while minimizing side effects. Although precision treatment has shown significant success in multiple cancer types, its application in HCC remains in its infancy. In this review, we discuss key aspects of precision treatment in HCC, including therapeutic biomarkers, molecular classifications, and the heterogeneity of the tumor microenvironment. We also propose future directions, ranging from revolutionizing current treatment methodologies to personalizing therapy through functional assays, which will accelerate the next phase of advancements in this area.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/therapy , Liver Neoplasms/drug therapy , Immunotherapy/methods , Tumor MicroenvironmentABSTRACT
The Kirsten rat sarcoma viral oncogene homologue KRAS is among the most commonly mutated oncogenes in human cancers, thus representing an attractive target for precision oncology. The approval for clinical use of the first selective inhibitors of G12C mutant KRAS therefore holds great promise for cancer treatment. However, despite initial encouraging clinical results, the overall survival benefit that patients experience following treatment with these inhibitors has been disappointing to date, pointing toward the need to develop more powerful combination therapies. Here, we show that responsiveness to KRASG12C and pan-RAS inhibitors in KRAS-mutant lung and colon cancer cells is limited by feedback activation of the parallel MAP2K4-JNK-JUN pathway. Activation of this pathway leads to elevated expression of receptor tyrosine kinases that reactivate KRAS and its downstream effectors in the presence of drug. We find that the combination of sotorasib, a drug targeting KRASG12C, and the MAP2K4 inhibitor HRX-0233 prevents this feedback activation and is highly synergistic in a panel of KRASG12C-mutant lung and colon cancer cells. Moreover, combining HRX-0233 and sotorasib is well-tolerated and resulted in durable tumor shrinkage in mouse xenografts of human lung cancer cells, suggesting a therapeutic strategy for KRAS-driven cancers.
Subject(s)
Antineoplastic Agents , Colonic Neoplasms , Lung Neoplasms , Humans , Animals , Mice , Proto-Oncogene Proteins p21(ras)/genetics , Precision Medicine , Antineoplastic Agents/pharmacology , Oncogenes , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , MAP Kinase Kinase 4ABSTRACT
BACKGROUND & AIMS: Despite the increasing number of treatment options available for liver cancer, only a small proportion of patients achieve long-term clinical benefits. Here, we aim to develop new therapeutic approaches for liver cancer. METHODS: A compound screen was conducted to identify inhibitors that could synergistically induce senescence when combined with cyclin-dependent kinase (CDK) 4/6 inhibitor. The combination effects of CDK4/6 inhibitor and exportin 1 (XPO1) inhibitor on cellular senescence were investigated in a panel of human liver cancer cell lines and multiple liver cancer models. A senolytic drug screen was performed to identify drugs that selectively killed senescent liver cancer cells. RESULTS: The combination of CDK4/6 inhibitor and XPO1 inhibitor synergistically induces senescence of liver cancer cells in vitro and in vivo. The XPO1 inhibitor acts by causing accumulation of RB1 in the nucleus, leading to decreased E2F signaling and promoting senescence induction by the CDK4/6 inhibitor. Through a senolytic drug screen, cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells. Up-regulation of CRBN was a vulnerability of senescent liver cancer cells, making them sensitive to CRBN-based PROTAC drugs. Mechanistically, we find that ubiquitin specific peptidase 2 (USP2) directly interacts with CRBN, leading to the deubiquitination and stabilization of CRBN in senescent liver cancer cells. CONCLUSIONS: Our study demonstrates a striking synergy in senescence induction of liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy.
Subject(s)
Adaptor Proteins, Signal Transducing , Cellular Senescence , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase 6 , Exportin 1 Protein , Karyopherins , Liver Neoplasms , Protein Kinase Inhibitors , Receptors, Cytoplasmic and Nuclear , Ubiquitin-Protein Ligases , Humans , Cellular Senescence/drug effects , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/metabolism , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Karyopherins/antagonists & inhibitors , Karyopherins/metabolism , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Receptors, Cytoplasmic and Nuclear/metabolism , Ubiquitin-Protein Ligases/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Cell Line, Tumor , Protein Kinase Inhibitors/pharmacology , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Animals , Retinoblastoma Binding Proteins/metabolism , Retinoblastoma Binding Proteins/genetics , Drug Synergism , Senotherapeutics/pharmacology , Xenograft Model Antitumor Assays , Signal Transduction/drug effects , Proteolysis/drug effects , Hydrazines/pharmacology , Hydrazines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Hep G2 Cells , Mice , Piperazines , Pyridines , TriazolesABSTRACT
PURPOSE: At the primary analysis, the APHINITY trial reported a statistically significant but modest benefit of adding pertuzumab to standard adjuvant chemotherapy plus trastuzumab in patients with histologically confirmed human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer. This study evaluated whether the 80-gene molecular subtyping signature (80-GS) could identify patients within the APHINITY population who derive the most benefit from dual anti-HER2 therapy. METHODS: In a nested case-control study design of 1,023 patients (matched event to control ratio of 3:1), the 80-GS classified breast tumors into functional luminal type, HER2 type, or basal type. Additionally, 80-GS distinguished tumor subtypes that exhibited a single-dominant functional pathway versus tumors with multiple activated pathways. The primary end point was invasive disease-free survival (IDFS). Hazard ratios (HRs) were evaluated by Cox regression. After excluding patients without appropriate consent and those with missing data, 964 patients were included. RESULTS: The 80-GS classified 50% (n = 479) of tumors as luminal type, 28% (n = 275) as HER2 type, and 22% (n = 209) as basal type. Most luminal-type tumors (86%) displayed a single-activated pathway, whereas 49% of HER2-type and 42% of basal-type tumors were dual activated. There was no significant difference in IDFS among different conventional 80-GS subtypes (single- and dual-activated subtypes combined). However, basal single-subtype tumors were significantly more likely to have an IDFS event (hazard ratio, 1.69 [95% CI, 1.12 to 2.54]) compared with other subtypes. HER2 single-subtype tumors displayed a trend toward greater beneficial effect on the addition of pertuzumab (hazard ratio, 0.56 [95% CI, 0.27 to 1.16]) compared with all other subtypes. CONCLUSION: The 80-GS identified subgroups of histologically confirmed HER2-positive tumors with distinct biological characteristics. Basal single-subtype tumors exhibit an inferior prognosis compared with other subgroups and may be candidates for additional therapeutic strategies. Preliminary results suggest patients with HER2-positive, genomically HER2 single-subtype tumors may particularly benefit from added pertuzumab, which warrants further investigation.