Features of tumor-microenvironment images predict targeted therapy survival benefit in patients with EGFR-mutant lung cancer

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are effective for many patients with lung cancer with EGFR mutations. However, not all patients are responsive to EGFR TKIs, including even those harboring EGFR-sensitizing mutations. In this study, we quantified the cells and cellular interaction features of the tumor microenvironment (TME) using routine H&E-stained biopsy sections. These TME features were used to develop a prediction model for survival benefit from EGFR TKI therapy in patients with lung adenocarcinoma and EGFR-sensitizing mutations in the Lung Cancer Mutation Consortium 1 (LCMC1) and validated in an independent LCMC2 cohort. In the validation data set, EGFR TKI treatment prolonged survival in the predicted-to-benefit group but not in the predicted-not-to-benefit group. Among patients treated with EGFR TKIs, the predicted-to-benefit group had prolonged survival outcomes compared with the predicted not-to-benefit group. The EGFR TKI survival benefit positively correlated with tumor-tumor interaction image features and negatively correlated with tumor-stroma interaction. Moreover, the tumor-stroma interaction was associated with higher activation of the hepatocyte growth factor/MET-mediated PI3K/AKT signaling pathway and epithelial-mesenchymal transition process, supporting the hypothesis of fibroblast-involved resistance to EGFR TKI treatment.     

MERTK activation drives osimertinib resistance in EGFR-mutant non–small cell lung cancer

Acquired resistance is inevitable in non–small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. The MERTK ligand GAS6 promoted downstream oncogenic signaling in EGFR-mutated (EGFR^MT) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, resensitized GAS6-treated NSCLC cells to OSI. Both GAS6 and EGF stimulated downstream PI3K/AKT and MAPK/ERK signaling in parental cells, but only GAS6 activated these pathways in OSI-resistant (OSIR) derivative cell lines. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling. Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFR^MT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naive and EGFR^MT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFR^MT NSCLC.     

HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy

Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide and available therapies, including immunotherapies, are ineffective for many patients. HCC is characterized by intratumoral hypoxia, and increased expression of hypoxia-inducible factor 1α (HIF-1α) in diagnostic biopsies is associated with patient mortality. Here we report the development of 32-134D, a low-molecular-weight compound that effectively inhibits gene expression mediated by HIF-1 and HIF-2 in HCC cells, and blocks human and mouse HCC tumor growth. In immunocompetent mice bearing Hepa1-6 HCC tumors, addition of 32-134D to anti-PD1 therapy increased the rate of tumor eradication from 25% to 67%. Treated mice showed no changes in appearance, behavior, body weight, hemoglobin, or hematocrit. Compound 32-134D altered the expression of a large battery of genes encoding proteins that mediate angiogenesis, glycolytic metabolism, and responses to innate and adaptive immunity. This altered gene expression led to significant changes in the tumor immune microenvironment, including a decreased percentage of tumor-associated macrophages and myeloid-derived suppressor cells, which mediate immune evasion, and an increased percentage of CD8⁺ T cells and natural killer cells, which mediate antitumor immunity. Taken together, these preclinical findings suggest that combining 32-134D with immune checkpoint blockade may represent a breakthrough therapy for HCC.     

A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60

Mitochondrial proteostasis, regulated by the mitochondrial unfolded protein response (UPR^mt), is crucial for maintenance of cellular functions and survival. Elevated oxidative and proteotoxic stress in mitochondria must be attenuated by the activation of a ubiquitous UPR^mt to promote prostate cancer (PCa) growth. Here we show that the 2 key components of the UPR^mt, heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease P (ClpP, a mitochondrial protease), were required for the development of advanced PCa. HSP60 regulated ClpP expression via c-Myc and physically interacted with ClpP to restore mitochondrial functions that promote cancer cell survival. HSP60 maintained the ATP-producing functions of mitochondria, which activated the β-catenin pathway and led to the upregulation of c-Myc. We identified a UPR^mt inhibitor that blocked HSP60’s interaction with ClpP and abrogated survival signaling without altering HSP60’s chaperonin function. Disruption of HSP60-ClpP interaction with the UPR^mt inhibitor triggered metabolic stress and impeded PCa-promoting signaling. Treatment with the UPR^mt inhibitor or genetic ablation of Hsp60 inhibited PCa growth and progression. Together, our findings demonstrate that the HSP60-ClpP–mediated UPR^mt is essential for prostate tumorigenesis and the HSP60-ClpP interaction represents a therapeutic vulnerability in PCa.     

Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian cancer

Ovarian cancer is characterized by aberrant activation of the mitogen-activated protein kinase (MAPK), highlighting the importance of targeting the MAPK pathway as an attractive therapeutic strategy. However, the clinical efficacy of MEK inhibitors is limited by intrinsic or acquired drug resistance. Here, we established patient-derived ovarian cancer models resistant to MEK inhibitors and demonstrated that resistance to the clinically approved MEK inhibitor trametinib was associated with enhancer reprogramming. We also showed that enhancer decommissioning induced the downregulation of negative regulators of the MAPK pathway, leading to constitutive ERK activation and acquired resistance to trametinib. Epigenetic compound screening uncovered that HDAC inhibitors could alter the enhancer reprogramming and upregulate the expression of MAPK negative regulators, resulting in sustained MAPK inhibition and reversal of trametinib resistance. Consequently, a combination of HDAC inhibitor and trametinib demonstrated a synergistic antitumor effect in vitro and in vivo, including patient-derived xenograft mouse models. These findings demonstrated that enhancer reprogramming of the MAPK regulatory pathway might serve as a potential mechanism underlying MAPK inhibitor resistance and concurrent targeting of epigenetic pathways and MAPK signaling might provide an effective treatment strategy for advanced ovarian cancer.     

FOXA1 overexpression suppresses interferon signaling and immune response in cancer

Androgen receptor–positive prostate cancer (PCa) and estrogen receptor–positive luminal breast cancer (BCa) are generally less responsive to immunotherapy compared with certain tumor types such as melanoma. However, the underlying mechanisms are not fully elucidated. In this study, we found that FOXA1 overexpression inversely correlated with interferon (IFN) signature and antigen presentation gene expression in PCa and BCa patients. FOXA1 bound the STAT2 DNA-binding domain and suppressed STAT2 DNA-binding activity, IFN signaling gene expression, and cancer immune response independently of the transactivation activity of FOXA1 and its mutations detected in PCa and BCa. Increased FOXA1 expression promoted cancer immuno- and chemotherapy resistance in mice and PCa and BCa patients. These findings were also validated in bladder cancer expressing high levels of FOXA1. FOXA1 overexpression could be a prognostic factor to predict therapy resistance and a viable target to sensitize luminal PCa, BCa, and bladder cancer to immuno- and chemotherapy.     

非小细胞肺癌的EGFR表达与EGFR基因突变的比较

目的探讨非小细胞肺癌（NSCLC）表皮生长因子受体（EGFR）免疫组化表达与EGFR基因突变的关系及其临床意义。方法对130例手术切除的非小细胞肺癌组织应用免疫组化方法检测EGFR表达,同时应用基因测序方法检测EGFR基因突变,研究EGFR表达与EGFR基因突变的关系。结果130例NSCLC中有38例EGFR基因突变,突变率为29．2％。EGFR阳性率为67．7％。EGFR表达与基因突变无关（P〉0．05）,结论EGFR免疫组化表达与EGFR基因突变无关,不能作为筛选EGFR酪氨酸激酶抑制剂（TKI）治疗NSCLC的指标。     

EGFR-TKI在EGFR突变非小细胞肺癌治疗中的应用现状及进展

表皮生长因子受体（EGFR）突变是非小细胞肺癌（NSCLC）中最常见的致癌驱动因素。表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）广泛应用于肺癌治疗中,特别是晚期NSCLC的一线治疗,与标准化疗相比,EGFR-TKI单药治疗已获得较好的疗效及耐受性。而EGFR-TKI在新辅助治疗、辅助治疗及晚期一线与其他药物联合治疗中的疗效尚未明确,获得性耐药成为了限制其疗效的主要问题。分子靶向治疗是驱动基因指导下的治疗,开启了非鳞非小细胞肺癌“个体化”与“精准”治疗时代。本文就EGFR-TKI治疗NSCLC的临床价值及耐药机制进行综述。     

EGFR mutations and EGFR tyrosine kinase inhibition in non-small cell lung cancer

OBJECTIVES: To discuss selected molecular targets and new clinical variables that can serve as both predictive and prognostic markers for outcome in patients with non-small cell lung cancer (NSCLC) treated with EGFR-TKIs. DATA SOURCES: Research and journal articles. CONCLUSION: In the near future, treatment for NSCLC will rely ever increasingly on molecular targets rather than empirically chosen cytotoxic chemotherapy for some patients. This will improve outcomes for patients with NSCLC. IMPLICATIONS FOR NURSING PRACTICE: An understanding of the molecular targets and clinical variables that are predictive and prognostic of outcome in NSCLC will help nurses better care for these patients.     

Respective limits of palliative care and oncology in the supportive care of cancer patients

 Advanced cancer patients develop a number of devastating physical and psychosocial symptoms before death. In recent years, there have been great advances in our knowledge on the appropriate assessment and management of many of the physical and psychosocial symptoms. There is also increasing understanding on the need for patients and families to receive appropriate follow-up and to have access to multiple settings for optimal care. Unfortunately, both models developed on the basis of palliative care/hospice and those developed on the basis of supportive care/oncology have failed to achieve these goals. Future models for the delivery of supportive cancer care will have to consider the need to ensure that patients receive a consistent level of assessment and management up to the time of death, that there is appropriate flexibility, to allow patients to access multiple levels of care in the trajectory of their illness, and that there is a significant contribution to the body of knowledge and future education of health care professionals. These programs will need to develop individually for each country with due consideration for the structure of the health care system, the structure of the academic system, and the financing of health care in different regions of the world. Published online: 23 June 1999     

An update on biomarkers for kinase inhibitor response in non-small-cell lung cancer

Introduction: The discovery of activating genetic and their use as predictive biomarkers for targeted therapy, such as tyrosine kinase inhibitors (TKIs), has changed the treatment paradigm of non-small cell lung cancer (NSCLC). As a result, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) TKIs have become the standard first-line treatment. Since then, other kinds of targetable oncogenic alterations have been identified in NSCLC. Several novel, molecularly-targeted TKIs have now achieved regulatory approval, while many others are currently in early- or late-phase clinical trial testing. These TKIs have significantly impacted and changed clinical outcomes for advanced NSCLC.

Areas covered: In this review, the authors discuss recent evidence and progress in targeted therapies, especially small molecular tyrosine kinase inhibitors, matched with their biomarkers for the treatment of advanced NSCLC.

Expert commentary: Although targeted therapies dramatically improve the outcome of patients with NSCLC harboring specific oncogenic alterations, molecular and clinical resistance almost invariably develops. New TKIs specifically active in molecular subgroups of NSCLC or the resistance setting have now been developed. The development of additional TKIs and rational combinations may further improve outcomes of NSCLC.     

RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11

Ferroptosis, an iron-dependent nonapoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA-binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here, we report that the RNA-binding protein RBMS1 participates in lung cancer development via mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 is a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3′- and 5′-UTR of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake, and promoted ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potential and clinical value.     

江西地区非小细胞肺癌EGFR基因突变分析

目的探讨江西地区非小细胞肺癌(NSCLC)患者表皮生长因子受体(EGFR)基因突变类型、突变率及其与临床特征的关系。方法收集2014年3月至2015年6月南昌大学第一附属医院非小细胞肺癌患者石蜡包埋组织78例,采用等位基因特异性扩增-聚合酶链反应(ARMS-PCR)方法,对非小细胞肺癌患者肿瘤组织EGFR基因18~21外显子突变进行检测,并分析其突变类型、突变发生率及其与临床特征之间的关系。结果在78例非小细胞肺癌患者中,共有27例发生EGFR基因突变,总突变率为34.6%。其中,第18、19、20、21号外显子突变率分别2.6%(2/78),12.8%(10/78),3.9%(3/78),14.1%(11/78)。一例既有21号外显子突变,又有20号外显子突变,其中,19号外显子的突变均为第746~750密码子的碱基缺失,21号外显子突变类型以L858R为主,且19号外显子的突变率与21号外显子的突变率无统计学差异(P0.05),女性EGFR基因的突变率显著高于男性,不吸烟者显著高于吸烟者,腺癌患者显著高于鳞癌患者(P0.05),而EGFR基因的突变率与非小细胞肺癌患者的年龄、临床分期无相关性(P0.05)。结论江西地区的非小细胞肺癌EGFR基因突变以19、21号外显子为主,常见于女性、不吸烟、腺癌的非小细胞肺癌患者。