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Cancer Research Sep 2023Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been...
UNLABELLED
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 antitumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.
SIGNIFICANCE
KRAS-mutant pancreatic cancer models, including KRAS inhibitor-resistant models, show exquisite sensitivity to combined pan-ERBB and KRAS targeting, which provides the rationale for testing this drug combination in clinical trials.
Topics: Mice; Animals; Afatinib; ErbB Receptors; Proto-Oncogene Proteins p21(ras); Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Mutation; Cell Line, Tumor
PubMed: 37378556
DOI: 10.1158/0008-5472.CAN-23-1313 -
Translational Lung Cancer Research Jul 2023This review will provide an overview of and mutations in non-small-cell lung cancer (NSCLC) with a focus on recent clinical approvals. (Review)
Review
BACKGROUND AND OBJECTIVE
This review will provide an overview of and mutations in non-small-cell lung cancer (NSCLC) with a focus on recent clinical approvals.
METHODS
We obtained data from the literature in accordance with narrative review reporting guidelines.
KEY CONTENT AND FINDINGS
mutations are present in up to 15-20% of all NSCLCs; amongst these, 10% correspond to kinase domain insertions in exon 20. Structurally similar, () mutations occurs in 1-4% of NSCLCs, mostly consisting of insertions or point mutations. The majority of exon 20 insertions occur within the loop following the regulatory C-helix and activate the kinase domain of EGFR without generating a therapeutic window to gefitinib, erlotinib, afatinib, dacomitinib or osimertinib. Mobocertinib represents a novel class of covalent EGFR inhibitors with a modest therapeutic window to these mutants and induces anti-tumor responses in a portion of patients [at 160 mg/day: response rate of <30% with duration of response (DoR) >17 months and progression-free survival (PFS) of >7 months] albeit with mucocutaneous and gastrointestinal toxicities. The bi-specific EGFR-MET antibody amivantamab-vmjw has modest but broad preclinical activity in EGFR-driven cancers and specifically for exon 20 insertion-mutated NSCLC has response rates <40% and PFS of <8.5 months at the cost of both infusion-related plus on-target toxicities. Both drugs were approved in 2021. The clinical development of kinase inhibitors for -mutated NSCLC has been thwarted by mucocutaneous/gastrointestinal toxicities that preclude a pathway for drug approval, as the case of poziotinib. However, the activation of ERBB2 has allowed for repurposing of antibody-drug conjugates (ADCs) that target ERBB2 with cytotoxic payloads. The FDA approved fam-trastuzumab deruxtecan-nxki in 2022 for NSCLC based on response rate of >55%, DoR >9 months, PFS >8 months and manageable adverse events (including cytopenias, nausea and less commonly pneumonitis). Other therapies in clinical development include sunvozertinib and zipalertinib, among others. In addition, traditional cytotoxic chemotherapy has some activity in these tumors.
CONCLUSIONS
The approvals of mobocertinib, amivantamab, and trastuzumab deruxtecan represent the first examples of precision oncology for exon 20 insertion-mutated and -mutated NSCLCs.
PubMed: 37577308
DOI: 10.21037/tlcr-23-98 -
Bladder (San Francisco, Calif.) 2023Urothelial carcinoma (UC) represents a common malignancy of the urinary system that can involve the kidneys, ureter, bladder, and urethra. Advanced/metastatic UC (mUC)... (Review)
Review
Urothelial carcinoma (UC) represents a common malignancy of the urinary system that can involve the kidneys, ureter, bladder, and urethra. Advanced/metastatic UC (mUC) tends to have a poor prognosis. UC ranks third in terms of human epidermal growth factor receptor 2 (HER2) overexpression among all tumors. However, multiple studies found that, unlike breast cancer, variable degrees of HER2 positivity and poor consistency between HER2 protein overexpression and gene amplification have been found. Trials involving trastuzumab, pertuzumab, lapatinib, afatinib, and neratinib have failed to prove their beneficial effect in patients with HER2-positive mUC, and a clinical trial on T-DM1 (trastuzumab emtansine) was terminated prematurely because of the adverse reactions. However, a phase II trial showed that RC48-ADC was effective. In this review, we provided an in-depth overview of the advances in the research regarding HER2-targeted therapy and the role of HER2 in mUC. Furthermore, we also discussed the prospects of potential strategies aimed at overcoming anti-HER2 resistance, and summarize the novel anti-HER2 approaches for the management of mUC used in recent clinical trials.
PubMed: 38155921
DOI: 10.14440/bladder.2023.871 -
Nature Communications Aug 2023Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients...
Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment.
Topics: Humans; Afatinib; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Lung Neoplasms; Mutation; Neoadjuvant Therapy; Protein Kinase Inhibitors; Tumor Microenvironment
PubMed: 37537219
DOI: 10.1038/s41467-023-40349-z -
European Journal of Cancer (Oxford,... Jul 2023This phase I/expansion study assessed the safety, pharmacokinetics and preliminary antitumor activity of afatinib in paediatric patients with cancer.
AIM
This phase I/expansion study assessed the safety, pharmacokinetics and preliminary antitumor activity of afatinib in paediatric patients with cancer.
METHODS
The dose-finding part enroled patients (2-<18 years) with recurrent/refractory tumours. Patients received 18 or 23 mg/m/d afatinib orally (tablet or solution) in 28-d cycles. In the maximum tolerated dose (MTD) expansion, eligible patients (1-<18 years) had tumours fulfilling ≥2 of the following criteria in the pre-screening: EGFR amplification; HER2 amplification; EGFR membrane staining (H-score>150); HER2 membrane staining (H-score>0). The primary end-points were dose-limiting toxicities (DLTs), afatinib exposure, and objective response.
RESULTS
Of 564 patients pre-screened, 536 patients had biomarker data and 63 (12%) fulfilled ≥2 EGFR/HER2 criteria required for inclusion in the expansion part. A total of 56 patients were treated (17 in the dose-finding and 39 in the expansion part). DLTs were observed in one of six MTD-evaluable patients receiving 18 mg/m²/d and in two of five MTD-evaluable patients receiving 23 mg/m²/d; 18 mg/m²/d was defined as the MTD. There were no new safety signals. Pharmacokinetics confirmed exposure consistent with the approved dose in adults. One partial response (-81% per Response Assessment in Neuro-Oncology) was observed in a patient with a glioneuronal tumour harbouring a CLIP2::EGFR fusion; unconfirmed partial responses were observed in two patients. In total, 25% of patients experienced objective response or stable disease (95% confidence interval: 14-38).
CONCLUSION
Targetable EGFR/HER2 drivers are rare in paediatric cancers. Treatment with afatinib led to a durable response (>3 years) in one patient with a glioneuronal tumour with CLIP2::EGFR fusion.
Topics: Child; Humans; Afatinib; Antineoplastic Combined Chemotherapy Protocols; ErbB Receptors; Neoplasms; Child, Preschool; Adolescent
PubMed: 37178647
DOI: 10.1016/j.ejca.2023.04.007 -
Oncotarget Mar 2024Here, I suggest that while first-line osimertinib extends median progression-free survival (PFS) in EGFR-mutant lung cancer compared to first-generation TKIs, it reduces...
Here, I suggest that while first-line osimertinib extends median progression-free survival (PFS) in EGFR-mutant lung cancer compared to first-generation TKIs, it reduces individual PFS in 15-20% of patients compared to first-generation TKIs. Since detecting a single resistant cell before treatment is usually impossible, osimertinib must be used in all patients as a first-line treatment, raising median PFS overall but harming some. The simplest remedy is a preemptive combination (PC) of osimertinib and gefitinib. A comprehensive PC (osimertinib, afatinib/gefitinib, and capmatinib) could dramatically increase PFS for 80% of patients compared to osimertinib alone, without harming anyone. This article also explores PCs for MET-driven lung cancer.
Topics: Humans; Gefitinib; Acrylamides; Afatinib; Lung Neoplasms; Aniline Compounds; Indoles; Pyrimidines
PubMed: 38497774
DOI: 10.18632/oncotarget.28569 -
Journal of Biomedical Science Nov 2023Although stimulating autophagy caused by UV has been widely demonstrated in skin cells to exert cell protection, it remains unknown the cellular events in UVA-treated...
BACKGROUND
Although stimulating autophagy caused by UV has been widely demonstrated in skin cells to exert cell protection, it remains unknown the cellular events in UVA-treated retinal pigment epithelial (RPE) cells.
METHODS
Human ARPE-19 cells were used to measure cell viability, mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP), mitochondrial mass and lysosomal mass by flow cytometry. Mitochondrial oxygen consumption rate (OCR) was recorded using Seahorse XF flux analyzer. Confocal microscopic images were performed to indicate the mitochondrial dynamics, LC3 level, and AMPK translocation after UVA irradiation.
RESULTS
We confirmed mitochondrial ROS production and DNA damage are two major features caused by UVA. We found the cell death is prevented by autophagy inhibitor 3-methyladenine and gene silencing of ATG5, and UVA induces ROS-dependent LC3II expression, LC3 punctate and TFEB expression, suggesting the autophagic death in the UVA-stressed RPE cells. Although PARP-1 inhibitor olaparib increases DNA damage, ROS production, and cell death, it also blocks AMPK activation caused by UVA. Interestingly we found a dramatic nuclear export of AMPK upon UVA irradiation which is blocked by N-acetylcysteine and olaparib. In addition, UVA exposure gradually decreases lysosomal mass and inhibits cathepsin B activity at late phase due to lysosomal dysfunction. Nevertheless, cathepsin B inhibitor, CA-074Me, reverses the death extent, suggesting the contribution of cathepsin B in the death pathway. When examining the role of EGFR in cellular events caused by UVA, we found that UVA can rapidly transactivate EGFR, and treatment with EGFR TKIs (gefitinib and afatinib) enhances the cell death accompanied by the increased LC3II formation, ROS production, loss of MMP and mass of mitochondria and lysosomes. Although AMPK activation by ROS-PARP-1 mediates autophagic cell death, we surprisingly found that pretreatment of cells with AMPK activators (A769662 and metformin) reverses cell death. Concomitantly, both agents block UVA-induced mitochondrial ROS production, autophagic flux, and mitochondrial fission without changing the inhibition of cathepsin B.
CONCLUSION
UVA exposure rapidly induces ROS-PARP-1-AMPK-autophagic flux and late lysosomal dysfunction. Pre-inducing AMPK activation can prevent cellular events caused by UVA and provide a new protective strategy in photo-oxidative stress and photo-retinopathy.
Topics: Humans; AMP-Activated Protein Kinases; Autophagic Cell Death; Autophagy; Cathepsin B; Epithelial Cells; ErbB Receptors; Poly(ADP-ribose) Polymerase Inhibitors; Reactive Oxygen Species
PubMed: 37936170
DOI: 10.1186/s12929-023-00978-4 -
Neoplasia (New York, N.Y.) Sep 2023Afatinib, as the first-line treatment for non-small cell lung cancer (NSCLC), causes severe gastrointestinal adverse reactions that greatly affect patients' quality of...
Afatinib, as the first-line treatment for non-small cell lung cancer (NSCLC), causes severe gastrointestinal adverse reactions that greatly affect patients' quality of life and even potentially result in treatment discontinuation. Multiple dose adjustments and concomitant use of anti-diarrheal medications are commonly employed to manage diarrhea, also allowing for a recovery period between each adjustment. However, these approaches are based on empirical guidance and still have limitations. This study aims to explore reliable approaches to alleviate diarrhea by focusing on two strategies: adjusting the dosing regimen of afatinib itself and implementing combination therapy. In this study, we firstly revealed a dose-dependent relationship between afatinib-induced diarrhea and gastrointestinal epithelial damage, resulting in atrophy, reduced expression of tight junction proteins, and increased permeability. We further found that even after discontinuation of the medication, although the severity of diarrhea had improved to baseline, the tight junction proteins and permeability of the intestinal epithelium did not fully recover, and the pharmacokinetics studies showed that drug absorption significantly increased than normal. This indicated the recovery period was longer than expected and may accelerate the occurrence of subsequent episodes of diarrhea. Hence, it would be prudent to consider adjustments to the starting dose or the recovery interval. Furthermore, we initially investigated the relationship between DPP enzyme and afatinib-induced diarrhea and found a significant decrease in plasma DPP enzyme activity following afatinib-induced diarrhea. Subsequently, we conducted continuous treatment with sitagliptin and observed significant improvement in afatinib-induced diarrhea. We observed that sitagliptin can promote the production of anti-inflammatory factors, increase the expression of intestinal epithelial tight junction proteins, and improve intestinal microbiota, further validating the mechanism through the use of GLP-2 as GLP-2 receptor inhibitor. In conclusion, sitagliptin exhibits promising potential as a therapeutic option for managing afatinib-induced diarrhea. Taken together, our study provides valuable insights into alleviating afatinib-induced diarrhea through both afatinib medication adjustment and sitagliptin combination therapy.
Topics: Rats; Animals; Afatinib; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Sitagliptin Phosphate; Quality of Life; ErbB Receptors; Diarrhea
PubMed: 37567055
DOI: 10.1016/j.neo.2023.100922 -
Cellular & Molecular Biology Letters Jul 2023Fibulin-like extracellular matrix protein 2 (EFEMP2) has been reported to be related to the progression of various cancers. We have previously reported that EFEMP2 was...
BACKGROUND
Fibulin-like extracellular matrix protein 2 (EFEMP2) has been reported to be related to the progression of various cancers. We have previously reported that EFEMP2 was highly expressed in ovarian cancer and was strongly associated with poor prognosis in patients. This study intends to further explore its interacting proteins and possible downstream signaling pathways.
METHOD
The expression of EFEMP2 was detected by RT-qPCR, ICC and western blot in 4 kinds of ovarian cancer cells with different migration and invasion ability. Cell models with strong or weak EFEMP2 expression were constructed by lentivirus transfection. The effects of the down-regulation and up-regulation of EFEMP2 on the biological behavior of ovarian cancer cells were studied through in-vitro and in-vivo functional tests. The phosphorylation pathway profiling array and KEGG database analyses identified the downstream EGFR/ERK1/2/c-Jun signaling pathway and the programmed death-1 (PD-L1) pathway enrichment. Additionally, the protein interaction between EFEMP2 and EGFR was detected by immunoprecipitation.
RESULT
EFEMP2 was positively correlated with the invasion ability of ovarian cancer cells, its down-regulation inhibited the migrative, invasive and cloning capacity of cancer cells in vitro and suppressed the tumor proliferation and intraperitoneal diffusion in vivo, while its up-regulation did the opposite. Moreover, EFEMP2 could bind to EGFR to induce PD-L1 regulation in ovarian cancer, which was caused by the activation of EGFR/ERK1/2/c-Jun signaling. Similar to EFEMP2, PD-L1 was also highly expressed in aggressive cells and had the ability to promote the invasion and metastasis of ovarian cancer cells both in vitro and in vivo, and PD-L1 upregulation was partly caused by EFEMP2 activation. Afatinib combined with trametinib had an obvious effect of inhibiting the intraperitoneal diffusion of ovarian cancer cells, especially in the group with low expression of EFEMP2, while overexpression of PD-L1 could reverse this phenomenon.
CONCLUSION
EFEMP2 could bind to EGFR to activate ERK1/2/c-Jun pathway and regulate PD-L1 expression, furthermore PD-L1 was extremely essential for EFEMP2 to promote ovarian cancer cells invasion and dissemination in vitro and in vivo. Targeted therapy against the source gene EFEMP2 is our future research direction, which may better inhibit the invasion and metastasis of ovarian cancer cells.
Topics: Female; Humans; B7-H1 Antigen; Cell Line, Tumor; ErbB Receptors; Gene Expression Regulation, Neoplastic; MAP Kinase Signaling System; Ovarian Neoplasms; Signal Transduction; Extracellular Matrix Proteins
PubMed: 37420173
DOI: 10.1186/s11658-023-00471-8