Shenqi Fuzheng injection restores the sensitivity to gefitinib in non-small cell lung cancer by inhibiting the IL-22/STAT3/AKT pathway.

CONTEXT: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Gefitinib is a first-line treatment for NSCLC. However, its effectiveness is hindered by the development of drug resistance. At present, Shenqi Fuzheng injection (SFI) is widely accepted as an adjuvant therapy in NSCLC. OBJECTIVE: This study investigates the molecular mechanism of SFI when combined with gefitinib in regulating cell progression among EGFR-TKI-resistant NSCLC. MATERIALS AND METHODS: We established gefitinib-resistant PC9-GR cells by exposing gefitinib escalation from 10 nM with the indicated concentrations of SFI in PC9 cells (1, 4, and 8 mg/mL). Quantitative real-time polymerase chain reaction was performed to assess gene expression. PC9/GR and H1975 cells were treated with 50 ng/mL of interleukin (IL)-22 alone or in combination with 10 mg/mL of SFI. STAT3, p-STAT3, AKT, and p-AKT expression were evaluated using Western blot. The effects on cell proliferation, clonogenicity, and apoptosis in NSCLC cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation and flow cytometry assays. RESULTS: SFI treatment alleviated the development of gefitinib resistance in NSCLC. PC9/GR and H1975 cells treated with SFI significantly exhibited a reduction in IL-22 protein and mRNA overexpression levels. SFI effectively counteracted the activation of the STAT3/AKT signaling pathway induced by adding exogenous IL-22 to PC9/GR and H1975 cells. Moreover, IL-22 combined with gefitinib markedly increased cell viability while reducing apoptosis. In contrast, combining SFI with gefitinib and the concurrent treatment of SFI with gefitinib and IL-22 demonstrated the opposite effect. DISCUSSION AND CONCLUSION: SFI can be a valuable therapeutic option to address gefitinib resistance in NSCLC by suppressing the IL-22/STAT3/AKT pathway.

Real-world clinical analysis in 190 advanced NSCLC patients with uncommon EGFR mutations: A multi-center study.

Differently from epidermal growth factor receptor (EGFR) 19Del and L858R mutations, the panoramic description of uncommon EGFR mutations is far from mature. Our understanding of its population characteristics, treatment response, and drug resistance mechanisms needs urgent expansion and deepening. Our study enrolled 437 patients with non-small-cell lung cancer from four clinical centers and who had uncommon EGFR mutations. The clinical characteristics of all patients and the treatment outcomes of 190 advanced patients who received pharmacotherapy were analyzed. Moreover, the acquired resistance mechanisms were explored based on 53 tissue or liquid re-biopsy data in 45 patients. Patients with EGFR 20ins had a shorter survival time compared with patients with non-20ins mutations. In total, 149 cases had received EGFR-tyrosine kinase inhibitors (TKI); afatinib was significantly superior to other EGFR-TKIs both in ORR and mPFS in all uncommon mutations and especially in the L861Q group. The most common acquired drug resistance mechanism was MET amplification, followed by EGFR T790M, which was significantly different from common EGFR mutations.

Notch signaling pathway: architecture, disease, and therapeutics.

The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.

The influence of STK11 mutation on acquired resistance to immunotherapy in advanced non-small cell lung cancer with Lynch syndrome: a case report and literature review.

Immune checkpoint inhibitors (ICI) monotherapy or combination therapies have become increasingly popular in patients with advanced non-small cell lung cancer (NSCLC). However, there are still many unknowns concerning the predictive bio-markers and resistance mechanisms to immunotherapy. Patients with primary tumor STK11 mutation reportedly to have a lower response rate than the STK11 wild-type and possibly a primary resistance mechanism to ICIs. However, there is presently no data regarding the contribution of STK11 to acquired resistance to ICIs. Herein we report on a patient who was diagnosed with advanced lung squamous cell carcinoma accompanied by Lynch syndrome. The patient developed an STK11 mutation after receiving pembrolizumab as a first-line treatment. Programmed death ligand 1 (PD-L1) was highly expressed (50%) in the biopsy. HRAS Q61L and TP53 R158L were mainly detected. Unexpectedly, the patient carried an MSH6 heterozygous germline mutation, and was classified as proficient mismatch repair (pMMR). The patient subsequently received pembrolizumab (200 mg, ivgtt, q3w) as first line therapy and achieved stable disease (SD) as the best response. After eight treatment cycles, the patient suffered disease progression (PD), and an STK11 frameshift mutation was newly identified in his plasma circulating tumor deoxyribonucleic acid (ctDNA). This case study suggests that STK11 could contribute to pembrolizumab acquired resistance. Furthermore, the patient was also diagnosed with Lynch syndrome, which rarely occurs in lung cancer.

Coexisting of COX7A2L-ALK, LINC01210-ALK, ATP13A4-ALK and Acquired SLCO2A1-ALK in a Lung Adenocarcinoma with Rearrangements Loss During the Treatment of Crizotinib and Ceritinib: A Case Report.

ALK rearrangements account for ~5% of non-small-cell lung cancer (NSCLC). Numerous rearrangement partners have been discovered. Here, we describe a 53-year-old nonsmoker with NSCLC, in whom we identified four novel rearrangements. The patient was diagnosed as adenocarcinoma in the right middle lobe of lung, with metastases in subcarinal lymph node, ipsilateral lung, pleura and contralateral rib (cT4N2M1, stage IV). Next-generation sequencing (NGS) identified three baseline ALK fusions: COX7A2L-ALK (C[intragenic]:A20), LINC01210-ALK (L[intergenic]:A20) and ATP13A4-ALK (A9:A19). The patient exhibited 12 months of progression-free survival (PFS) and a partial response (PR) to first-line crizotinib therapy. We then discovered a new SLCO2A1-ALK fusion (S[intergenic]:A18) and a missense mutation C1156Y after resistance developed. Sequential ceritinib resulted in further 8 months of PFS, after which NGS results demonstrated the loss of ATP13A4-ALK and SLCO2A1-ALK. This is the first description a NSCLC patient harbors four ALK fusions and was sensitive to tyrosine kinase inhibitors (TKIs). Acquisition and loss of ALK fusions after ALK inhibitors may account for resistance.

Durable complete response after afatinib and crizotinib in an advanced non-small cell lung cancer patient with EGFR L861Q mutation and acquired MET amplification: a case report.

Epidermal growth factor receptor (EGFR) L861Q mutation is a non-classical mutation, with a low incidence, poor response, and uncertain resistance mechanisms when treated by an EGFR tyrosine kinase inhibitor (EGFR-TKI). The liver is one of the most common distant organs to metastasize in nonsmall cell lung cancer (NSCLC), and achieving complete remission treatment for the liver is difficult. In this report, a patient was diagnosed with advanced lung adenocarcinoma harboring the EGFR L861Q mutation and responded well to afatinib for 16 months. Complete response and partial response (PR) appeared in the liver metastasis and primary lesion respectively. Following this, afatinib plus crizotinib overcame the acquired resistance of MET amplification and brought about the complete remission of the liver for 10 months. Interestingly, the liver remission endured for 22 months and persisted even when the disease progressed and the EGFR T790M mutation emerged. To our knowledge, this is the first time that afatinib induced longterm liver remission in a patient with an EGFR non-classical mutation, and in whom crizotinib with afatinib proved to be a reliable treatment for overcoming MET amplification resistance with an EGFR non-classical mutation. This precise and individualized gene-based treatment significantly prolonged the survival time of this stage IV case with brain metastases yielding 26 months of progression-free survival (PFS) time and more than 3 years of overall survival time.