Receptor Tyrosine Kinase Inhibitor Research Articles

Evaluating the prognostic role of glucose-to-lymphocyte ratio in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors in first line: a study by the Turkish Oncology Group Kidney Cancer Consortium (TKCC).

Identifying prognostic indicators for risk stratification in metastatic renal cell carcinoma (mRCC) is crucial for optimizing treatment strategies and follow-up plans. This study aims to investigate the prognostic role of the glucose-to-lymphocyte ratio (GLR) in patients with mRCC receiving tyrosine kinase inhibitors (TKIs) as first-line therapy. A retrospective cohort study was conducted using data from the Turkish Oncology Group Kidney Cancer Consortium Database. GLR was calculated by dividing the fasting glucose (mmol/L) by the lymphocyte count (×109/L). We categorized patients into two categories based on their median GLR level. The analysis included a total of 598 patients. We found that progression-free survival (PFS) was significantly longer in the GLR-low group, with a median PFS of 15.05 months (95% CI 12.7-17.4) compared to 7.79 months (95% CI 6.6-9.0) in the GLR-high group (p < 0.001). Multivariate analysis identified GLR as an independent risk factor for poor PFS (HR 1.39, 95% CI 1.12-1.72; p = 0.003). Overall survival (OS) was also significantly longer in the GLR-low group, with a median OS of 38.47 months (95% CI, 30.9-46.0) compared to 24.15 months (95% CI 18.0-30.2) in the GLR-high group (p = 0.001). GLR was an independent predictor for OS in multivariate analysis (HR 1.45, 95% CI 1.12-1.86; p = 0.004). The GLR can be a valuable prognostic marker for glucose metabolism and systemic inflammatory status in this patient population. Our research highlights the potential prognostic value of GLR in patients with mRCC receiving TKIs, indicating its potential as a useful tool for clinical decision-making.

Clinical evaluation and outcome in heart failure patients receiving chemotherapy with different anti-cancer agents.

The optimal strategy for modern chemotherapy should be based on a comprehensive approach for cancer patients with cardiovascular diseases. Therefore, cardio-oncology has received increasing attention owing to the cardiotoxic effects of anti-cancer therapies. We aimed to evaluate the clinical characteristics and outcomes of patients with heart failure (HF) who received chemotherapy compared with those of a matched cohort with HF who did not receive chemotherapy, using real-world HF data. This study was based on the Diagnosis Procedure Combination (DPC) database of the Japanese Registry of All Cardiac and Vascular Diseases (JROAD). We identified 1328113 patients who were hospitalized for HF between April 2012 and March 2021. The propensity score (PS) was estimated using a logistic regression model, with chemotherapy as the dependent variable, and a clinically score-matched analysis of 11532 patients with HF with or without chemotherapy. The primary endpoint was readmission. Colon, lung, breast and prostate cancers accounted for >60% of all cancer types. After PS matching, readmission was significantly more frequently observed in patients with chemotherapy than those without [odds ratio (OR), 1.26; 95% confidence interval (CI) 1.17-1.36, P<0.01]. In particular, treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) (OR, 1.69; 95% CI 1.39-2.07), taxane (OR, 2.95; 95% CI 2.11-4.12), anthracyclines (OR, 1.86; 95% CI 1.19-2.90) and fluorouracil agents (OR, 1.65; 95% CI 1.18-2.30) caused a higher risk of readmission. Medical providers need to monitor and follow-up patients with HF, depending on the characteristics of the anti-cancer agents and types of cancer.

Pharmacokinetics, mass balance, and metabolism of [14C]PLB1004, a selective and irreversible EGFR-TKI in humans.

PLB1004, developed by Beijing Avistone Biotechnology Co., Ltd., is a safe, highly selective, and efficient irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) employed in treating non-small-cell-lung-cancer (NSCLC). This study investigated its pharmacokinetics, mass balance, and metabolism in 6 healthy Chinese male subjects treated with 160mg (70 µCi) [14C]PLB1004. Following drug administration, samples of blood, urine and feces were collected for quantitative determination of total radioactivity and metabolites were identified through radioactivity detection coupled with UHPLC-MS/MS. Following drug administration, the median radioactive Tmax was 4.17h in plasma, with the average t1/2 of PLB1004-related components in plasma of approximately 54.3h. Over 264h post-administration, the average cumulative excretion among the six subjects was 95.01% of the administered dose, with 84.71% and 10.30% excreted in feces and urine, respectively. Nine metabolites were characterized and identified and the parent drug PLB1004 was detected in plasma, urine, and feces. Among these metabolites, M689 was the most prevalent one in plasma, urine, and feces, constituting 25.37% of the total plasma radioactivity, and 55.88% and 1.73% of the administrated dose in feces and urine, respectively. Fecal excretion emerged as PLB1004 excretion route, while urinary excretion via the kidneys served as the secondary route. The primarily metabolic pathways are oxidation, demethylation, dehydrogenation, and cysteine conjugation in humans.

Effect of furmonertinib on the pharmacokinetics of rivaroxaban or apixaban in vivo.

Furmonertinib, a third generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), is used for non-small cell lung cancer (NSCLC). Rivaroxaban and apixaban are direct oral anticoagulants (DOACs) used for venous thromboembolism (VTE), which is a frequent comorbid with NSCLC. They are substrates of CYP3A4, P-gp and BCRP, whereas furmonertinib is an inhibitor of P-gp and BCRP. This study aimed to disclose the extent of effect of furmonertinib on the pharmacokinetics of rivaroxaban or apixaban. Rats were divided into four groups (n=6) that received rivaroxaban (group 1), furmonertinib and rivaroxaban (group 2), apixaban (group 3), furmonertinib and apixaban (group 4). The concentrations of drugs were measured by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Furmonertinib increased the Cmax and AUC0-t of rivaroxaban by 1.66 and 2.07-fold, whereas decreased the CLz/F by 1.70-fold and Vz/F 1.27-fold. Furthermore, furmonertinib caused similar changes in apixaban pharmacokinetics. The pharmacokinetic results suggest that it is essential to alert the effect of furmonertinib on the pharmacokinetics of rivaroxaban or apixaban in clinical practice.

Alternating Administration of Osimertinib for Leptomeningitis and Docetaxel Plus Ramucirumab for Lung Adenocarcinoma Resistant to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Case Report.

Traditionally, leptomeningitis (LM) has been considered untreatable and terminal, but the development of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has significantly improved the prognosis of patients with EGFR mutations. However, non-LM lesions occasionally progress or recur, even when the LM is successfully controlled with EGFR-TKIs, and treatment of such cases remains unclear. We herein report a patient with advanced non-small-cell lung cancer (NSCLC) who was treated with an EGFR-TKI for LM and cytotoxic chemotherapy for EGFR-TKI-resistant pulmonary lesions. The patient survived for almost four years after the diagnosis of LM, suggesting that this treatment may be beneficial in advanced NSCLC with EGFR-TKI-sensitive LM and EGFR-TKI-resistant extracranial lesions.

Unbiased Drug Target Prediction Reveals Sensitivity to Ferroptosis Inducers, HDAC and RTK Inhibitors in Melanoma Subtypes.

The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem. Here, we mine large-scale MM proteogenomic data to identify druggable targets and forecast treatment efficacy and resistance. Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC, and AKT1, across five distinct MM subtypes. These proteins are potential drug targets applicable to one or multiple MM subtypes. Additionally, by integrating proteogenomic profiles obtained from MM subtypes with MM cell line dependency and drug sensitivity data, we identified a total of 162 potentially targetable genes. Lastly, we identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype. Employing these unbiased approaches, we have uncovered compounds targeting ferroptosis demonstrating a striking 30× fold difference in sensitivity among different subtypes. Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy.

Orthoallosteric EGFR-TKIs: A New Paradigm in NSCLC Treatment Strategy Targeting the C797S Mutation.

The remarkable clinical success of third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has significantly advanced the treatment landscape for non-small-cell lung cancer (NSCLC). However, the emergence of the tertiary point mutation C797S poses a substantial obstacle to their clinical efficacy, leading to a dearth of FDA-approved targeted therapies for patients harboring this mutation. Addressing this pressing clinical challenge necessitates the development of novel therapeutic agents targeting the clinically challenging EGFR mutation. This review delves into the design strategies, antitumor activity, and crucial protein-drug interactions of recently introduced Orthoallosteric fourth-generation EGFR-TKIs. These inhibitors are distinguished by their ability to simultaneously engage both the canonical orthosteric (ATP) binding site and the allosteric site. By shedding light on these key aspects, the review serves as a valuable resource for medicinal chemists, empowering them to propel the advancement of fourth-generation EGFR inhibitors.

Epidermal growth factor receptor ligands enriched in follicular fluid exosomes promote oncogenesis of fallopian tube epithelial cells

BackgroundIncessant ovulation is the main etiologic factor of ovarian high-grade serous carcinomas (HGSC), which mostly originate from the fallopian tube epithelium (FTE). Receptor tyrosine kinase (RTK) ligands essential for follicle development and ovulation wound repair were abundant in the follicular fluid (FF) and promoted the transformation of FTE cells. This study determined whether RTK ligands are present in FF exosomes and whether epidermal growth factor receptor (EGFR) signaling is essential for oncogenic activity.MethodsThe FF of women undergoing in vitro fertilization was fractionated based on the richness of exosomes and tested for transformation toward FTE cells under different RTK inhibitors. EGFR ligands in FF exosomes were identified, and downstream signaling proteins in FTE cells were characterized.ResultsThe transforming activity of FF was almost exclusively enriched in exosomes, which possess a high capacity to induce anchorage-independent growth, clonogenicity, migration, invasion, and proliferation of FTE cells. EGFR inhibition abolished most of these activities. FF and FF exosome exposure markedly increased EGFR phosphorylation and the downstream signal proteins, including AKT, MAPK, and FAK. Multiple EGF family growth factors, such as amphiregulin, epiregulin, betacellulin, and transforming growth factor-alpha, were identified in FF exosomes.ConclusionsOur results demonstrate that FF exosomes serve as carriers of EGFR ligands as well as ligands of other RTKs that mediate the transformation of FTE cells and underscore the need to further explore the content and roles of FF exosomes in HGSC development.

Observational study of the efficacy and safety of first-line osimertinib and later treatments for uncommon epidermal growth factor receptor-activating mutation-positive advanced non-small cell lung cancer.

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is a first-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR mutations, including both sensitizing and T790M resistance mutations. Its real-world efficacy against uncommon EGFR mutations remains under-researched. The REIWA study, a multicentric, prospective, observational study conducted in Japan from September 2018 to August 2020, enrolled patients with advanced or recurrent EGFR mutation-positive NSCLC receiving osimertinib. Data on clinical outcomes, safety, disease progression, and subsequent treatments were collected for patients with uncommon EGFR mutations. Of 583 patients receiving osimertinib, 39 (6.7%) had an uncommon EGFR mutation. The present study included 32 of these patients after excluding seven patients with an exon 20 insertion mutation. The overall objective response rate was 53.1% [95% confidence interval (CI): 36.4-69.1], and the disease control rate was 78.1% (95% CI: 61.0-89.3). The median progression-free survival was 9.4months (95% CI: 5.0-20.0), and the median overall survival (OS) was 21.8 (95% CI: 14.4-NA) months. Notably, patients with an exon21 L861Q mutation had a significantly longer OS than those with an exon18 G719X mutation, the respective values being 37.8 and 9.7months (hazard ratio: 0.29; 95% CI: 0.10-0.85; P=0.02). The rate of grade 3 or worse adverse events was 10.3%. Seven out of 32 (21.9%) patients showed progression involving only the central nervous system. Osimertinib demonstrated efficacy and tolerability in the clinical setting in patients with uncommon EGFR mutation-positive NSCLC.

Patients with non‑small cell lung cancer with the exon 21 L858R mutation: From distinct mechanisms to epidermal growth factor receptor tyrosine kinase inhibitor treatments (Review).

The most common oncogenic driver in non-small cell lung cancer (NSCLC) is epidermal growth factor receptor (EGFR) gene mutations, which are more common in Asian (30-50%) than in Caucasian (10-15%) populations. Exon 19 deletion (ex19del) and exon 21 L858R (ex21 L858R) mutations account for ~45 and 40% of all EGFR mutations, respectively. Moreover, EGFR-tyrosine kinase inhibitors (TKIs) may be more effective and improve the quality of life of patients with NSCLC more than chemotherapy regimens. By contrast, patients with the ex21 L858R mutation may have a lower sensitivity and duration of response to EGFR-TKIs as well as a shorter survival compared with those with the ex19del mutation. However, current guidelines classify ex21 L858R and ex19del as the same condition and recommend the same treatment strategy for both. Aiming for precision medicine, the present review introduces and compares different EGFR-TKIs for the ex21 L858R mutation to assess more personalized treatment options for the population with this mutation.

TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing.

As a putative lung specific oncogene, the transducin-like enhancer of split 1 (TLE1) corepressor drives an anti-apoptotic and pro-epithelial-mesenchymal transition (EMT) gene transcriptional programs in human lung adenocarcinoma (LUAD) cells, thereby promoting anoikis resistance and tumor aggressiveness. Through its survival- and EMT-promoting gene regulatory programs, TLE1 may impact drug sensitivity and resistance in lung cancer cells. In the present study, a novel function of TLE1 was uncovered as an inhibitor of the antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) gefitinib in the human LUAD cell line A549, which exhibits moderate sensitivity to EGFR-TKI. While upregulation of TLE1 expression potently inhibited the proliferation inhibitory and apoptotic effects of gefitinib in A549 cells, downregulation of endogenous TLE1 in these cells enhanced their sensitivity to gefitinib. In experimentally derived gefitinib-resistant A549 cells (A549GR) that have acquired EMT, TLE1 expression is upregulated as compared with parental A549 cells, and acute ablation of TLE1 expression is sufficient to partially restore gefitinib sensitivity and attenuate EMT phenotype. Mechanistic studies showed that TLE1 confers gefitinib resistance in A549 cells in part via downregulation of E-cadherin, a known potentiator of EGFR-TKI sensitivity and apoptosis induction. Importantly, the TLE1/E-cadherin transcriptional axis is negatively regulated by gefitinib to trigger apoptosis via the Bcl-2-inhibitor of transcription 1 cell death pathway. In conclusion, these results indicate a novel role of TLE1 in modulating EGFR-TKI sensitivity in lung cancer cells via regulation of E-cadherin expression, and its upregulation may potentiate EGFR-TKI resistance in LUAD.

CKAP4 is a potential therapeutic target to overcome resistance to EGFR-TKIs in lung adenocarcinoma.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard treatments for non-small cell lung cancer (NSCLC) patients with EGFR mutations; however, drug resistance limits their efficacy. Cytoskeleton-associated protein 4 (CKAP4) has been linked to cancer progression, but its role in EGFR-TKI resistance remains unclear. This study investigates the clinical relevance of CKAP4 as a therapeutic target to overcome EGFR-TKI resistance in lung adenocarcinoma (LUAD) patients. GEO datasets were analyzed to identify 24 differentially expressed genes associated with EGFR-TKI resistance, with CKAP4 selected via functional annotation and scoring using the VarElect tool. The prognostic significance of CKAP4 was evaluated using public databases, and its upregulation was confirmed in osimertinib-tolerant H1975 cells through quantitative reverse transcription-polymerase chain reaction. Integrated bioinformatics analysis identified CKAP4 as strongly associated with EGFR-TKI resistance. Elevated CKAP4 expression was particularly linked to poorer clinical outcomes in LUAD patients. Notably, osimertinib-tolerant cells exhibited high CKAP4 expression, correlating positively with increased half-maximal inhibitory concentrations of EGFR-TKIs. LUAD patients with upregulated CKAP4 showed significantly reduced overall and relapse-free survival. This study underscores the prognostic value of CKAP4 in EGFR-mutated LUAD and highlights its potential as a therapeutic target to counter EGFR-TKI resistance.

Clinical outcomes of patients with EGFR-mutated NSCLC developing interstitial lung disease during first-line osimertinib therapy: a sub-analysis of the Reiwa study.

Osimertinib-induced interstitial lung disease in untreated EGFR-mutated, advanced non-small cell lung cancer is being reported at a higher rate in Japan than elsewhere. However, data on the interstitial lung disease incidence during first-line osimertinib therapy and the course of lung cancer treatments administered after interstitial lung disease onset in the real-world setting are scarce. The present study reviewed the data from the Reiwa study, a multicentric, observational study examining the efficacy and safety of first-line osimertinib therapy in the clinical setting. Patients with EGFR-mutated non-small cell lung cancer who began osimertinib therapy between September 2018 and August 2020 were enrolled and followed until August 2022. Among 583 patients receiving first-line osimertinib therapy, 75 (12.8%) had interstitial lung disease development, and 18 (3.0%) had at least grade 3 interstitial lung disease. Fifty-nine patients (78%) received some form of treatment following interstitial lung disease onset. An epidermal growth factor receptor-tyrosine kinase inhibitor rechallenge was performed in 31 patients (41%), with 18 (24%) receiving osimertinib again. Interstitial lung disease recurred in five (28%) of these 18 patients, none of 13 patients receiving another type of tyrosine kinase inhibitor, and seven (25%) of 28 patients receiving chemotherapy and/or immune checkpoint inhibitor therapy. The median overall survival after the initial osimertinib therapy was 38.4months and 12.2months for patients with interstitial lung disease grade 1-2 and grade 3-4, respectively (hazard ratio: 0.37; 95% confidence interval: 0.20-0.70; P=0.002). Patients with interstitial lung disease grade 3-4 had poorer survival during the first-line osimertinib therapy. A substantial risk of interstitial lung disease recurrence was associated with post-osimertinib therapy. Trial registration code: UMIN000038683.

The Impact of Bevacizumab and miR200c on EMT and EGFR-TKI Resistance in EGFR-Mutant Lung Cancer Organoids.

Objectives: This research aims to investigate the mechanisms of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC), particularly focusing on the role of the epithelial-mesenchymal transition (EMT) within the tumor microenvironment (TME). Materials and Methods: We employed an in vitro three-dimensional organoid model that mirrors the physiology of human lung cancer. These organoids consist of lung cancer cells harboring specific EGFR mutations, human mesenchymal stem cells, and human umbilical vein endothelial cells. We analyzed EMT and drug resistance markers, and evaluated the effects of the anti-angiogenic agent Bevacizumab and micro-RNA miR200c. Results: The study identified a significant link between EMT and EGFR-TKI resistance. Notable findings included a decrease in E-cadherin and an increase in Zinc Finger E-Box Binding Homeobox 1 (ZEB1), both of which influenced EMT and resistance to treatment. Bevacizumab showed promise in improving drug resistance and mitigating EMT, suggesting an involvement of the Vascular Endothelial Growth Factor (VEGF) cascade. Transfection with miR200c was associated with improved EMT and drug resistance, further highlighting the role of EMT in TKI resistance. Conclusions: Our research provides significant insights into the EMT-driven EGFR-TKI resistance in NSCLC and offers potential strategies to overcome resistance, including the use of Bevacizumab and miR200c. However, due to the limitations in organoid models in replicating precise human cancer TME and the potential influence of specific EGFR mutations, further in vivo studies and clinical trials are necessary for validation.

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

Non-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. We 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). We 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). This 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.

Plasma metabolomics profiling of EGFR-mutant NSCLC patients treated with third-generation EGFR-TKI

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the latest and a vital treatment option for non-small cell lung cancer (NSCLC) patients. Although EGFR-sensitive mutations are an indication for third-generation EGFR-TKI therapy, 30% of NSCLC patients lack response and all patients inevitably progress. There is a lack of biomarkers to predict the efficacy of EGFR-TKI therapy. In this report, we performed comprehensive plasma metabolomic profiling on 186 baseline and 20 post-treatment samples, analyzing 1,019 metabolites using four ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) methods. The dataset contains detailed clinical and metabolic information for 186 patients. Rigorous quality control measures were implemented. No significant differences in body mass index and biochemical metabolic parameters were observed between responders and non-responders. The datasets were utilized to characterize the responsive metabolic traits of third-generation EGFR-TKI therapy. All datasets are available for download on the OMIX website. We anticipate that these datasets will serve as valuable resources for future studies investigating NSCLC metabolism and for the development of personalized therapeutic strategies.

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.

Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using an In Silico Enabled Drug Discovery Platform.

Despite the success of first, second, and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer with classical EGFR mutations (L858R or Exon 19 deletions), disease progression occurs due to the acquisition of T790M and C797S resistance. Herein, we report a physics-based computationally driven lead identification approach that identified structurally unique imidazo[3.2-b]pyrazoles as reversible and wild-type-sparing EGFR TKIs of classical mutations bearing both T790M and C797S. During profiling of imidazo[3.2-b]pyrazoles, we elucidated the bioactivation mechanism causing CYP3A4/5 time-dependent inhibition (TDI) and found key modifications to mitigate the TDI. Compound 31 inhibited EGFR L858R/T790M/C797S in biochemical assays with a Ki = 2.1 nM and EGFR del19/T790M/C797S in a Ba/F3 cellular assay with an IC50 = 56.9 nM. The deuterated analogue of 31 (38) demonstrated dose-dependent tumor growth inhibition in a Ba/F3 EGFR del19/T790M/C797S CDX model by 47% at 50 mg/kg BID and 92% at 100 mg/kg BID.

TFF3 drives Hippo dependent EGFR-TKI resistance in lung adenocarcinoma.

Intrinsic and acquired resistance represent major obstacles to optimize outcomes in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeted therapy in lung adenocarcinoma (LUAD). Hence, a deeper understanding of EGFR-TKI resistance mechanisms in LUAD will potentially assist in formulating strategies to delay or overcome such resistance. Herein, it was observed that trefoil factor 3 (TFF3) is a crucial mediator of the LUAD EGFR-TKI response. TFF3 conferred intrinsic resistance to EGFR inhibition in LUAD by promotion of EGFR activation. TFF3 expression was also increased in acquired EGFR-TKI resistant LUAD, accompanied by reduced EGFR activation. YAP, a key mediator of the Hippo signaling, was positively regulated by TFF3 by post-transcriptional mechanisms and was responsible for acquired EGFR-TKI resistance mediated by TFF3. Inhibition of TFF3 by a small molecule inhibitor not only enhanced EGFR-TKI sensitivity in LUAD cells but also restored the sensitivity of acquired EGFR-TKI resistant LUAD cells to EGFR-TKIs in vitro and in vivo. These findings demonstrate a pivotal function of TFF3 in mediating both intrinsic and acquired EGFR-TKI resistance in LUAD and may offer a potential therapeutic mechanism for delaying or overcoming resistance to EGFR-TKIs.