miRNA Targeted Therapy in Lung Cancer

AbstractSmall cell lung cancer (SCLC) remains a deadly form of cancer, with a 5-year survival rate of less than 10 percent, necessitating novel therapies. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is emerging as a therapeutic target and is co-expressed with BCL2 in multiple tumor types due to microRNA coregulation. We hypothesize that ROR1-targeted therapy is effective in small cell lung cancer and synergizes with therapeutic BCL2 inhibition. Tissue microarrays (TMAs) and formalin-fixed paraffin-embedded (FFPE) SCLC patient samples were utilized to determine the prevalence of ROR1 and BCL2 expression in SCLC. Eight SCLC-derived cell lines were used to determine the antitumor activity of a small molecule ROR1 inhibitor (KAN0441571C) alone and in combination with the BCL2 inhibitor venetoclax. The Chou-Talalay method was utilized to determine synergy with the drug combination. ROR1 and BCL2 protein expression was identified in 93% (52/56) and 86% (48/56) of SCLC patient samples, respectively. Similarly, ROR1 and BCL2 were shown by qRT-PCR to have elevated expression in 79% (22/28) and 100% (28/28) of SCLC patient samples, respectively. KAN0441571C displayed efficacy in 8 SCLC cell lines, with an IC50 of 500 nM or less. Synergy as defined by a combination index of <1 via the Chou-Talalay method between KAN0441571C and venetoclax was demonstrated in 8 SCLC cell lines. We have shown that ROR1 inhibition is synergistic with BCL2 inhibition in SCLC models and shows promise as a novel therapeutic target in SCLC.

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Epidermal Growth Factor Receptor Expression and Resistance Patterns to Targeted Therapy in Non-Small Cell Lung Cancer: A Review

Cells ◽

10.3390/cells10051206 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1206

Author(s):

Emma-Anne Karlsen ◽

Sam Kahler ◽

Joan Tefay ◽

Shannon R. Joseph ◽

Fiona Simpson

Keyword(s):

Lung Cancer ◽

Epidermal Growth Factor Receptor ◽

Targeted Therapy ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Growth Factor Receptor ◽

Small Cell ◽

Small Cell Lung ◽

Resistance Patterns ◽

Epidermal Growth

Globally, lung cancer is the leading cause of cancer-related death. The majority of non-small cell lung cancer (NSCLC) tumours express epidermal growth factor receptor (EGFR), which allows for precise and targeted therapy in these patients. The dysregulation of EGFR in solid epithelial cancers has two distinct mechanisms: either a kinase-activating mutation in EGFR (EGFR-mutant) and/or an overexpression of wild-type EGFR (wt-EGFR). The underlying mechanism of EGFR dysregulation influences the efficacy of anti-EGFR therapy as well as the nature of resistance patterns and secondary mutations. This review will critically analyse the mechanisms of EGFR expression in NSCLC, its relevance to currently approved targeted treatment options, and the complex nature of secondary mutations and intrinsic and acquired resistance patterns in NSCLC.

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Surgical choice of non-small cell lung cancer with unexpected pleural dissemination intraoperatively

BMC Cancer ◽

10.1186/s12885-021-08180-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Junjie Hu ◽

Yan Chen ◽

Xinsheng Zhu ◽

Qiang Ma ◽

Jing Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Small Cell Lung Cancer ◽

Distant Metastasis ◽

Survival Benefit ◽

Tumor Resection ◽

Small Cell ◽

Small Cell Lung ◽

Systematic Lymphadenectomy ◽

Cox Analysis

Abstract Background Whether patients with non-small cell lung cancer (NSCLC) with unexpected pleural dissemination (UPD) could get survival benefit from tumor resection remained controversial. Methods Totally, 169 patients with NSCLC with UPD were included between 2012 and 2016. Patients were divided into the tumor resection and open-close group. Progression-free survival (PFS) and overall survival (OS) were compared with a log-rank test. The multivariable Cox analysis was applied to identify prognostic factors. Results Sixty-five patients received open-close surgery and 104 patients underwent main tumor and visible pleural nodule resection. Tumor resection significantly prolonged OS (hazard ratio [HR]: 0.408, P < 0.001), local PFS (HR: 0.283, P < 0.001), regional PFS (HR: 0.506, P = 0.005), and distant metastasis (HR: 0.595, P = 0.032). Multivariable Cox analysis confirmed that surgical method was an independent prognostic factor for OS, local PFS and regional PFS, except distant metastasis. Subgroup analyses indicated that tumor resection could not improve OS in the patients who received targeted therapy (HR: 0.649, P = 0.382), however, tumor resection was beneficial for the patients who received adjuvant chemotherapy alone (HR: 0.322, P < 0.001). In the tumor resection group, lobectomy (HR: 0.960, P = 0.917) and systematic lymphadenectomy (HR: 1.512, P = 0.259) did not show survival benefit for OS. Conclusions Main tumor and visible pleural nodule resection could improve prognosis in patients with UPD who could not receive adjuvant targeted therapy. Sublobar resection without systematic lymphadenectomy may be the optimal procedure.

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