Tyrosine Kinase Inhibitors Research Articles

PFKFB3-dependent redox homeostasis and DNA repair support cell survival under EGFR-TKIs in non-small cell lung carcinoma

BackgroundThe efficacy of tyrosine kinase inhibitors (TKIs) targeting the EGFR is limited due to the persistence of drug-tolerant cell populations, leading to therapy resistance. Non-genetic mechanisms, such as metabolic rewiring, play a significant role in driving lung cancer cells into the drug-tolerant state, allowing them to persist under continuous drug treatment.MethodsOur study employed a comprehensive approach to examine the impact of the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) on the adaptivity of lung cancer cells to EGFR TKI therapies. We conducted metabolomics to trace glucose rerouting in response to PFKFB3 inhibition during TKI treatment. Live cell imaging and DCFDA oxidation were used to quantify levels of oxidation stress. Immunocytochemistry and Neutral Comet assay were employed to evaluate DNA integrity in response to therapy-driven oxidative stress.ResultsOur metabolic profiling revealed that PFKFB3 inhibition significantly alters the metabolic profile of TKI-treated cells. It limited glucose utilization in the polyol pathway, glycolysis, and TCA cycle, leading to a depletion of ATP levels. Furthermore, pharmacological inhibition of PFKFB3 overcome TKI-driven redox capacity by diminishing the expression of glutathione peroxidase 4 (GPX4), thereby exacerbating oxidative stress. Our study also unveiled a novel role of PFKFB3 in DNA oxidation and damage by controlling the expression of DNA-glycosylases involved in base excision repair. Consequently, PFKFB3 inhibition improved the cytotoxicity of EGFR-TKIs by facilitating ROS-dependent cell death.ConclusionsOur results suggest that PFKFB3 inhibition reduces glucose utilization and DNA damage repair, limiting the adaptivity of the cells to therapy-driven oxidative stress and DNA integrity insults. Inhibiting PFKFB3 can be an effective strategy to eradicate cancer cells surviving under EGFR TKI therapy before they enter the drug-resistant state. These findings may have potential implications in the development of new therapies for drug-resistant cancer treatment.

Screening, Synthesis and Biological Evaluation of Novel Bruton’s Tyrosine Kinase Inhibitors

Screening, Synthesis and Biological Evaluation of Novel Bruton’s Tyrosine Kinase Inhibitors

Chiglitazar diminishes the warburg effect through PPARγ/mTOR/PKM2 and increases the sensitivity of imatinib in chronic myeloid leukemia

BackgroundA tyrosine kinase inhibitor (TKI) such as Imatinib (IM) is the preferred treatment for Chronic Myeloid Leukemia (CML). However, the emergence of IM resistance presents a significant challenge to disease management. A characteristic of cancer cells, including IM-resistant CMLs, are characterized by heightened uptake of glucose and aberrant glycolysis in the cytosol, which is known as the Warburg effect. In addition to its potential to modulate the Warburg effect, Chiglitazar (Chi), a compound that regulates glucose metabolism, has also been investigated for its implication in cancer treatment. This suggests that combining Chi with IM may be a therapeutic strategy for overcoming IM resistance in CML.MethodsSensitive and IM-resistance CML cells were treated with Chi in vitro, followed by detecting of extracellular acidification rate (ECAR) using a Seahorse XF Analyzer. CML cell proliferation, cell cycle distribution, and apoptosis were tested by CCK-8 assay and flow cytometry. RNA sequencing was utilized to investigate potential transcriptional changes induced by Chi usage. In vivo studies were conducted on immunodeficient mice implanted with CML cells and given Chi and/or IM later. Tumor growth was monitored, as well as tumor burden and survival rates between groups.ResultsOur metabonomic, transcriptomic, and molecular biology studies demonstrated that Chi, in part, diminished the Warburg effect by reducing glucose and lactate production in imatinib-resistant CML cells through the PPARγ/mTOR/PKM2 pathway. This modulation of glucose metabolism resulted in reduced cell proliferation and enhanced sensitivity to IM in imatinib-resistant CML cells in vitro. Rescue assay by introducing shPPARγ or mTOR activator verified the underlying regulatory pathway. Also, the combination of Chi and IM synergistically increased the sensitivity of IM in vivo and prolonged the survival of imatinib-resistance CML transplanted mice.ConclusionsOur results demonstrated the potential of Chi to overcome IM resistance in vitro and in vivo. By inhibiting the Warburg effect through the PPARγ/mTOR/PKM2 pathway, Chi resensitizes CML cells towards imatinib treatment. Combining IM with Chi is an alternative therapeutic option for CML management, especially for IM-resistant CML patients.

Effectiveness of systemic treatments for advanced non-clear cell renal cell carcinoma: a systematic review and meta-analysis

BackgroundNon-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous group of malignancies with substantial differences in morphology, genetic profiles, clinical behavior, and prognosis. Optimal treatment for nccRCC remains unclear, largely extrapolated from evidence available for clear cell renal cell carcinoma (ccRCC). This study aimed to compare the efficacy of current mainstream drug treatments for nccRCC to provide clinical treatment guidance for advanced cases.MethodsWe systematically searched PubMed, Embase, and Cochrane databases for trials published up to January 2, 2024, including controlled and single-arm trials. Primary outcomes included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).ResultsWe selected six randomized controlled trials (RCTs) comparing mammalian target of rapamycin inhibitors (mTORi) with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). These trials included four first-line and two second-line studies, with a total of 398 advanced nccRCC patients. Pooled results showed that VEGFR-TKIs significantly improved PFS compared to mTORi in first-line treatment (relative risk [RR] = 1.387; 95% confidence interval [CI]: 1.04-1.85; p = 0.026). In a single-arm meta-analysis, we included 22 VEGFR-TKI trials, three mTORi trials, 12 immune checkpoint inhibitor (ICI) therapies, five chemotherapy trials, and 10 combination therapy trials. The pooled ORR ranged from 6% (95% CI: 0–16%) to 36% (95% CI: 27–44%), and the pooled DCR ranged from 54% (95% CI: 50–58%) to 81% (95% CI: 70–91%). Subgroup analysis of ICI showed a higher ORR in the PD-L1 positive group compared to the PD-L1 negative group (RR = 3.044; 95% CI: 1.623-5.709; p = 0.001).ConclusionThis systematic review and meta-analysis demonstrate that VEGFR-TKIs improve PFS in first-line treatment compared to mTORi. The single-arm meta-analysis suggest that combination therapies with different mechanisms result in better ORR and DCR. Furthermore, PD-L1 positive patients showed significantly better therapeutic responses with ICI treatment than PD-L1 negative patients.

Asciminib add-on to imatinib demonstrates sustained high rates of ongoing therapy and deep molecular responses with prolonged follow-up in the ASC4MORE study

BackgroundUp to 65% of patients with chronic myeloid leukemia (CML) who are treated with imatinib do not achieve sustained deep molecular response, which is required to attempt treatment-free remission. Asciminib is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket. This unique mechanism of action allows asciminib to be combined with adenosine triphosphate–competitive tyrosine kinase inhibitors to prevent resistance and enhance efficacy. The phase II ASC4MORE trial investigated the strategy of adding asciminib to imatinib in patients who have not achieved deep molecular response with imatinib.MethodsIn ASC4MORE, 84 patients with CML in chronic phase not achieving deep molecular response after ≥ 1 year of imatinib therapy were randomized to asciminib 40 or 60 mg once daily (QD) add-on to imatinib 400 mg QD, continued imatinib 400 mg QD, or switch to nilotinib 300 mg twice daily.ResultsMore patients in the asciminib 40- and 60-mg QD add-on arms (19.0% and 28.6%, respectively) achieved MR4.5 (BCR::ABL1 ≤ 0.0032% on the International Scale) at week 48 (primary endpoint) than patients in the continued imatinib (0.0%) and switch to nilotinib (4.8%) arms. Fewer patients discontinued asciminib 40- and 60-mg QD add-on treatment (14.3% and 23.8%, respectively) than imatinib (76.2%, including crossover patients) and nilotinib (47.6%). Asciminib add-on was tolerable, with rates of AEs and AEs leading to discontinuation less than those with nilotinib, although higher than those with continued imatinib (as expected in these patients who had already been tolerating imatinib for ≥ 1 year). No new or worsening safety signals were observed with asciminib add-on vs the known asciminib monotherapy safety profile.ConclusionsOverall, these results support asciminib add-on as a treatment strategy to help patients with CML in chronic phase stay on therapy to safely achieve rapid and deep response, although further investigation is needed before this strategy is incorporated into clinical practice.Trial registrationNCT03578367

FGFR-Altered Urothelial Carcinoma: Resistance Mechanisms and Therapeutic Strategies.

Fibroblast growth factor receptor (FGFR) 2/3 alterations have been implicated in tumorigenesis in several malignancies, including urothelial carcinoma. Several FGFR inhibitors have been studied or are in development, and erdafitinib is the sole inhibitor to achieve regulatory approval. Given the rapidly evolving treatment landscape for advanced urothelial carcinoma, including regulatory approvals and withdrawals, determining the most appropriate treatment strategies and sequencing for FGFR-altered urothelial carcinoma is becoming increasing critical. However, the clinical efficacy of FGFR inhibitors is limited by acquired resistance similar to that seen with other tyrosine kinase inhibitors. Additional challenges to the clinical use of FGFR inhibitors include treatment-related adverse events and the financial costs associated with treatment. In this review, we describe known mechanisms of FGFR inhibitor resistance, including gatekeeper mutations, domain mutations, and the development of new mutations. In addition, we discuss management strategies, including ongoing clinical trials evaluating FGFR inhibitors, antibody-drug conjugates, and combination therapies with immune checkpoint inhibitors that may provide additional treatment options for localized and metastatic urothelial carcinoma.

A good response to furmonertinib fourth-line treatment of an advanced lung adenocarcinoma patient with EGFR exon20in and PIK3CA mutation: a case report and literature review

BackgroundLung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), is the most prevalent cancer globally and remains the leading cause of cancer-related mortality. Epidermal growth factor receptor (EGFR) mutations, frequently observed in female NSCLC patients, have revolutionized treatment strategies with the advent of tyrosine kinase inhibitors (TKIs). These therapies significantly improve survival and are considered the standard of care for patients harboring EGFR mutations. However, most patients eventually develop resistance to EGFR-TKIs, leading to disease progression. Resistance mechanisms are classified as either EGFR-dependent or EGFR-independent, the latter involving bypass pathway activation, including dysregulation of downstream signaling cascades. EGFR-independent resistance often renders all EGFR-TKIs ineffective, necessitating further investigation into resistance mechanisms.Case summaryWe report the case of a 63-year-old Chinese woman diagnosed with synchronous lung adenocarcinoma harboring an EGFR exon 21 far-loop insertion mutation and clear cell renal cell carcinoma (ccRCC). A multidisciplinary team recommended systemic therapy for the lung adenocarcinoma and clinical observation for ccRCC. First-line treatment with bevacizumab plus pemetrexed-carboplatin achieved a progression-free survival (PFS) of 7 months. Second-line treatment with sintilimab and nedaplatin resulted in a PFS of 4.9 months. Third-line therapy with sintilimab and anlotinib proved ineffective. In the fourth line, the patient received furmonertinib, a third-generation EGFR-TKI, based on the FAVOUR trial. This treatment achieved durable disease control with excellent tolerability, yielding a PFS of 27 months and ongoing clinical benefit.ConclusionThis case demonstrates that furmonertinib can provide significant clinical benefit to NSCLC patients with complex resistance mechanisms, including those involving the PIK3CA/mTOR pathway. These findings support its potential to overcome EGFR-TKI resistance and warrant further investigation in similar clinical contexts.

Development of the serotonin release assay with enterochromaffin cell-rich human intestinal organoids for the risk evaluation of drug-induced emesis.

Drug-induced emesis is one of the major symptoms of gastrointestinal toxicity. Preclinical risk assessment of emesis has been challenging owing to the lack of suitable animal models or in vitro assay systems. One of the triggers of emesis is an excessive serotonin (5-HT) release from enterochromaffin (EC) cells in the intestinal tract, which activates the vomiting center in the brain stem and elicits the vomiting reflex. Here, we propose a 5-HT release assay using human jejunal organoids that are preferentially differentiated into EC cells. In this assay, EC cell-rich organoids were stimulated with emetic risk drugs, and 5-HT release into the media was quantified, along with cellular ATP level and LDH leakage. Anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitors (TKIs) have been reported to exhibit different probabilities of emesis in clinical settings. We demonstrated that 5-HT release from EC cell-rich organoids could qualitatively distinguish between drugs with high or low emetic risk. The results indicated that 5-HT release by ALK/ROS1-TKIs tended to occur prior to the onset of LDH leakage from EC cell-rich organoids, suggesting that 5-HT release was not simply a result of cell bursting. Epidermal growth factor receptor (EGFR) TKIs exhibit a lower potency for inducing 5-HT release, which is consistent with their low emetic risk. In summary, the use of EC cell-rich organoids in 5-HT release assays may prove to be a valuable tool in predicting drug-induced emesis in humans during the drug development.

Osimertinib for Epidermal Growth Factor Receptor Exon 20 Insertion and Exon 21Osimertinib for Epidermal Growth Factor Receptor Exon 20 Insertion and Exon 21 L858R Mutations in Lung Adenocarcinoma L858R Mutations in Lung Adenocarcinoma

Patients with lung adenocarcinoma harbouring epidermal growth factor receptor (EGFR) mutations are usually treated with tyrosine kinase inhibitors (TKIs). However, patients with lung adenocarcinoma harbouring EGFR exon 20 insertion mutations are generally resistant to TKIs. Herein, we report the case of a woman who presented with right shoulder pain for 6 months after undergoing left lower lobectomy for lung adenocarcinoma in 2017. Imaging revealed extensive disease spread, and biopsy confirmed adenocarcinoma, with EGFR exon 20 insertion and exon 21 L858R mutations. After treatment with palliative intensity-modulated radiotherapy to the right shoulder, the patient was prescribed osimertinib 80mg. However, a month into the treatment, the patient developed neutropenia. Osimertinib was discontinued and later restarted at half the initial dose. The patient subsequently showed a dramatic improvement in both haematological and oncological parameters, suggesting that reduced-dose osimertinib is effective for patients with adenocarcinoma harbouring EGFR exon 20 insertion and exon 21 L858R mutations.

Clinical and biomarker analyses of SHR-1701 combined with famitinib in patients with previously treated advanced biliary tract cancer or pancreatic ductal adenocarcinoma: a phase II trial

Advanced biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC) have poor prognoses and limited treatment options. Here, we conducted this first-in-class phase II study to evaluate the efficacy and safety of SHR-1701, a bifunctional fusion protein targeting programmed death-ligand 1 (PD-L1) and transforming growth factor-beta (TGF-β), combined with famitinib, a multi-targeted receptor tyrosine kinase inhibitor, in patients with advanced BTC or PDAC who failed previous standard treatment (trial registration: ChiCTR2000037927). Among 51 enrolled patients, the BTC cohort showed an objective response rate (ORR) of 28% (including 2 complete responses) and a disease control rate (DCR) of 80%, with a median progression-free survival (mPFS) of 5.1 months and a median overall survival (mOS) of 16.0 months. In the PDAC cohort, the ORR was 15% (2 complete responses), with a DCR of 60%, and the mPFS and mOS were 2.1 months and 5.3 months, respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 29.4% of patients, with no grade 5 TRAEs reported. Exploratory analyses revealed that primary tumor resection history, peripheral blood immunophenotype changes, and distinct immune-metabolic profiles were associated with treatment benefits. An immune/metabolism score integrating the features of six genes was developed as a predictive biomarker for immunotherapy response in multiple cohorts, allowing for the selection of patients most likely to experience positive outcomes from this therapy regimen. In conclusion, our study provides proof-of-concept data supporting the potential of SHR-1701 plus famitinib as an effective and safe subsequent-line therapy for refractory BTC and PDAC, highlighting the promise of targeting PD-L1, TGF-β, and angiogenesis pathways simultaneously.

Persist or resist: Immune checkpoint inhibitors in EGFR-mutated NSCLC.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), especially third-generation TKIs, have significantly improved the progression-free survival and overall survival of non-small cell lung cancer (NSCLC) patients with EGFR mutation, TKI resistance is inevitable for most patients. Over the past few years, immune checkpoint inhibitors (ICIs) have significantly improved the survival for EGFR-wild type NSCLC patients. However, no significantly improved benefits were observed with ICI monotherapy in EGFR-mutated patients. EGFR-mutated NSCLC shows more heterogeneity in tumor mutational burden (TMB), programmed cell death-ligand 1 (PD-L1), and immune microenvironment characteristics. Whether ICIs are suitable for EGFR-mutated NSCLC patients remains to be elucidated. In this review, we summarized clinical trials of ICIs or combined therapy in EGFR-mutated NSCLC patients. We further discussed the factors determining the efficacy of ICIs in EGFR-mutated NSCLC patients, the mutation subtypes and microenvironment characteristics of potential responders. More importantly, we provided insights into areas worth further investigation in the future.

Growth retardation and adult height in pediatric patients with chronic-phase chronic myeloid leukemia treated with tyrosine kinase inhibitors.

Growth retardation and adult height in pediatric patients with chronic-phase chronic myeloid leukemia treated with tyrosine kinase inhibitors.

PRMT1 Promotes the Self-renewal of Leukemia Stem Cells by Regulating Protein Synthesis.

The application of tyrosine kinase inhibitors (TKIs) has revolutionized the management of chronic myeloid leukemia (CML). However, disease relapse and progression particularly due to persistent leukemia stem cells (LSCs) remain a big challenge in the clinic. Therefore, validation of the therapeutic vulnerability in LSCs is urgently needed. This study verifies the critical role of protein arginine methyltransferase 1 (PRMT1) in the maintenance of CML LSCs. It is found that PRMT1 promotes the survival and serially plating abilities of human primary CML LSCs. Genetic deletion of Prmt1 significantly delays the leukemogenesis and impairs the self-renewal of LSCs in BCR-ABL-driven CML mice. PRMT1 regulates LSCs and leukemia development depending on its methyltransferase activity. Pharmacological inhibition of PRMT1 activity by MS023 remarkably eliminates LSCs and prolongs the survival of CML mice. Mechanistical studies reveal that PRMT1 promotes transcriptional activation of ribosomal protein L29 (RPL29) via catalyzing asymmetric dimethylation of histone H4R3 (H4R3me2a) at its gene promoter region. PRMT1 augments the global protein synthesis via RPL29 in CML LSCs. Taken together, the findings provide new evidence that histone arginine methylation modification regulates protein synthesis in LSCs and highlight PRMT1 as a valuable druggable target for patients with CML.

Live Cell Imaging of Human Liver Fibrosis using Hepatic Micro-Organoids.

Due to the limitations of available in vitro systems and animal models, we lack a detailed understanding of the pathogenetic mechanisms and have minimal treatment options for liver fibrosis. Therefore, we engineered a live cell imaging system that assesses fibrosis in a human multi-lineage hepatic organoid in a microwell (i.e., microHOs). Transcriptomic analysis revealed that TGFβ1 converted mesenchymal cells in microHOs into myofibroblast-like cells resembling those in fibrotic human liver tissue. When pro-fibrotic intracellular signaling pathways were examined, the anti-fibrotic effect of receptor-specific tyrosine kinase inhibitors was limited to the fibrosis induced by the corresponding growth factor, which indicates their anti-fibrotic efficacy would be limited to fibrotic diseases solely mediated by that growth factor. Based upon transcriptomic and transcription factor activation analyses in microHOs, GSK3β and p38 MAPK inhibitors were identified as potential new broad-spectrum therapies for liver fibrosis. Other new therapies could subsequently be identified using the microHO system.

A Phase 2 study of Savolitinib in Patients with MET Amplified Metastatic Colorectal Cancer.

MET amplification (amp) is a driver of acquired resistance to epidermal growth factor receptor (EGFR) antibodies in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). Savolitinib is an oral small molecule tyrosine kinase inhibitor that has demonstrated anti-tumor activity in MET-driven advanced solid tumors. We report the results of a phase 2 study of savolitinib in patients with mCRC with MET amp detected by circulating cell free (cf)DNA. Patients with chemotherapy refractory mCRC and MET amp detected by cfDNA were treated with savolitinib until unacceptable toxicity or disease progression. The primary endpoint was objective response rate. Secondary endpoints were clinical activity and safety. Five patients were enrolled and treated. Best overall response was stable disease (SD) in two patients, progressive disease (PD) in two patients, and one patient unevaluable for response. The majority of treatment-emergent adverse events (TEAEs) were grade 1 or 2. The most common TEAEs included fatigue (n = 3) and nausea (n = 3). There were no grade 4 or 5 TEAEs. Savolitinib was well tolerated; however, in this small group of biomarker-selected patients, we observed no evidence of anti-tumor activity. Clinicaltrials.gov Identifier: NCT03592641. Registered on July 17, 2018.

Abstract A011: Discovery and characterization of the first highly potent and selective AXL receptor tyrosine kinase inhibitor AB801

Abstract The AXL receptor (AXL) is a transmembrane protein that is highly expressed in a variety of tumors and correlates with poor prognosis in cancer patients. AXL is expressed in cancer, immune, and stromal cells and has been implicated in the development of resistance to chemotherapy, targeted therapies, and immunotherapies. Activation of AXL by either its ligand, growth arrest specific protein 6 (GAS6), or ligand-independent homo- and hetero-dimerization facilitates AXL phosphorylation and initiates signaling cascades that promote cancer cell proliferation, survival, and an immunosuppressive microenvironment. Historically, most small-molecule inhibitors capable of suppressing AXL signaling are unselective and inhibit several other related kinases. Administration of a truly selective AXL inhibitor would be expected to be free of the off-target toxicity of other kinase inhibitors; this, in turn, might allow the unmasking of the full therapeutic benefit associated with robust AXL inhibition. To this end, we initiated a medicinal chemistry campaign with additional goals of discovering a potent and orally bioavailable inhibitor. Through iterative SAR-guided design we discovered AB801, a reversible AXL inhibitor. Importantly, AB801 exhibits excellent selectivity against MERTK, TYRO3 (closely related tyrosine kinases) and the overall kinome. AB801 exhibits a double-digit picomolar inhibitory constant and retains significant activity in cell-based assays performed in 100% human serum. In vitro, AB801 increases sensitivity to standard of care (SOC) therapeutics such as chemotherapy and results in increased DNA damage, leading to cancer cell death. AB801 treatment also sensitizes tumors to immune checkpoint blockade by increasing immune cell activation. Significant anti-tumor efficacy is observed in combination with SOC therapies in multiple in vivo models. When compared against existing AXL inhibitors such as bemcentinib, AB801 shows large improvements in both potency and selectivity. A placebo-controlled phase 1 study (NCT06004921) to assess the safety and pharmacokinetics of AB801 in healthy volunteers was recently completed; AB801 was well tolerated at all tested doses and exhibited a dose-proportionate increase in exposure. Currently, AB801 is in clinical evaluation in patients with advanced cancer (NCT06120075). Citation Format: Dillon H. Miles, Corinne N. Foley, Shiwei Qu, Dillon H. Miles, Srinivas Paladugu, Ehesan U. Sharif, Joice Thomas, Pradeep Nareddy, Guiling Zhao, Rebecca Grange, Manmohan R. Leleti, Jay P. Powers, Stefan Garrido-Shaqfeh, Ada Chen, Hema Singh, Yue Tong Lee, Xiaoning Zhao, David Green, Hsin-Ting Huang, Lixia Jin, Jhansi Leslie, Logan Chinn, Susan L Paprcka, Ester Fernandez-Salas. Discovery and characterization of the first highly potent and selective AXL receptor tyrosine kinase inhibitor AB801 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A011.

Efficacy and safety of lenvatinib plus gefitinib in lenvatinib-resistant hepatocellular carcinomas: a prospective, single-arm exploratory trial

Lenvatinib, a multi-kinase inhibitor, has been approved as first-line treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is limited. We have shown previously that lenvatinib and epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) combination therapy overcomes lenvatinib resistance in HCC with high level of EGFR expression (EGFRhigh). We present here the results of a single-arm, open-label, exploratory study of lenvatinib plus the EGFR-TKI gefitinib for patients with HCC resistance to lenvatinib (NCT04642547; n = 30). Only patients with EGFRhigh HCC and progressive disease after lenvatinib treatment were recruited in the study. The most frequent adverse events of all grades were fatigue (27 patients; 90%), followed by rash (25 patients; 83.3%), diarrhea (24 patients; 80%), and anorexia (12 patients; 40%). Among 30 patients, 9 (30%) achieved a confirmed partial response and 14 (46.7%) had stable disease according to mRECIST criteria. Based on RECIST1.1, 5 (16.7%) achieved a confirmed partial response and 18 (60%) had stable disease. The estimated median progression free survival (PFS) and overall survival (OS) time were 4.4 months (95% CI: 2.5 to 5.9) and13.7 months (95% CI: 9.0 to NA), respectively. The objective response rate (ORR) of the patients in the present study compares very favorable to that seen for the two approved second line treatments for HCC (cabozantinib ORR of 4%; regorafenib ORR of 11%). Given that this combination was well-tolerated, a further clinical study of this combination is warranted.

The Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer

Lung cancer has emerged as a highly aggressive malignancy posing a significant global health hazard, with a particular concern for the rising incidence and mortality of gene-altered non-small cell lung cancer (NSCLC). As the prevalence of NSCLC rises, the investigation and selection of tumor treatment techniques are gaining significance. The treatment of individuals with genetic mutations in advanced NSCLC has emphasized the application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Early and subsequent generations of EGFR-TKIs have demonstrated clinical efficacy in NSCLC patients carrying select genetic alterations. Osimertinib, a third-generation EGFR-TKI, has been sanctioned as the standard first-line therapy and is also utilized as a second-line option for individuals who develop the T790M resistance mutation following prior EGFR-TKI treatment. Approximately 10 to 30 percent of patients diagnosed with NSCLC exhibit EGFR mutations. This leads to abnormal activation of cancer genes and inactivation of tumor suppressor genes, resulting in poor prognosis for patients. This paper aims to analyze the development and resistance processes of EGFR inhibitors, thereby enhancing the comprehension of the resistance pathways to EGFR-TKIs.

In silico design, modelling and molecular mechanisms of Axl receptor tyrosine kinase inhibitors

A kinase domain from receptor tyrosine kinases (RTKs) regulate intracellular communications to control cellular metabolic activities. Some of the malignant cells have upregulated and overexpressed RTKs which are responsible for angiogenesis in many metastatic cancers. Axl RTK is present in most of the eukaryotic cells and all metastatic cancer cells have overexpressed Axl tyrosine kinase to trigger uncontrolled growth and angiogenesis in the malignant cells. The upregulated kinases can be inhibited in its active and inactive states in the presence of small organic molecule inhibitors. Kinase inhibitors have been discovered to arrest the signal transduction pathways in the malignant cells as a therapy and cure for cancer. In this work, small molecule databases were screened using the pharmacophore features of a macrocyclic inhibitor (7YS) taken as reference from the crystal structure of Axl kinase domain. Pharmacophore based virtual screening of small molecule libraries (CHEMBL32, ChemDiv, Chemspace, Mcule, MolProt, PubChem and Zinc), followed by molecular docking, molecular dynamics simulations, binding energies from MM-PBSA calculations and trajectory analysis as principal component analysis were studied. The molecular basis for the binding of macrocyclic inhibitor, ATP and seven screened hit molecules bound at Axl kinase domain in two different modes at catalytic and regulatory sites was analyzed.

Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages.

The combination of epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) leads to an increased incidence of severe immune-related adverse events (irAEs). However, the mechanisms underlying macrophages in irAEs have not been elucidated. An osimertinib and ICI-induced irAE mouse model was constructed. Lung micro-CT scans were used to assess the degree of inflammatory infiltration. Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues. Flow cytometry was used to detect the percentages of T cells, NK cells, and macrophages and the expression of EGFR. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum interleukin (IL)-6, alanine transaminase (ALT), ferritin, and tumor necrosis factor (TNF)-α levels. Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq. Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state. Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6, ALT, and ferritin levels. RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group. Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6, ALT, and ferritin levels in the combination treatment group. An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages, which led to the release of relevant cytokines.