Chemotherapy Response In Lung Cancer Research Articles

Depletion of tumor-associated macrophages inhibits lung cancer growth and enhances the antitumor effect of cisplatin.

In lung cancer, tumor-associated macrophages (TAMs), especially M2-like TAMs, represent the main tumor progression components in the tumor microenvironment (TME). Therefore, M2-like TAMs may serve as a therapeutic target. The purpose of this study was to investigate the effect of M2-like TAM depletion in the TME on tumor growth and chemotherapy response in lung cancer. The levels of secreted monocyte chemoattractant protein (MCP-1) and prostaglandin E2 (PGE2) in the supernatants of lung cancer cell lines A549 and LLC were evaluated via ELISA. Cell migration assays were performed to assess the recruitment ability of macrophage cell lines THP-1 and J774-1 cells. Differentiation of macrophages was assessed via flow cytometry. Immunohistochemical staining was performed to visualize M2-like TAMs in transplanted lung cancer in mouse. We used the COX-2 inhibitor nimesulide to inhibit the secretion of MCP-1 and PGE2, which promotes macrophage migration and M2-like differentiation. Nimesulide treatment decreased the secretion of MCP-1 and PGE2 from lung cancer cells. Nimesulide treatment suppressed the migration of macrophages by blocking MCP-1. Lung cancer supernatant induced the differentiation of macrophages toward the M2-like phenotype, and nimesulide treatment inhibited M2-like differentiation by blocking MCP-1 and PGE2. In the lung cancer mouse model, treatment with nimesulide depleted M2-like TAMs in the TME and enhanced the tumor inhibitory effect of cisplatin. Our results indicated that blocking the secretion of MCP-1 and PGE2 from tumor cells depleted M2-like TAMs in the TME and the combination therapy with cisplatin considerably suppressed tumor growth in the LLC mouse model.

TTN/TP53 mutation might act as the predictor for chemotherapy response in lung adenocarcinoma and lung squamous carcinoma patients.

BackgroundChemotherapy is the preferred treatment in many types of cancer including lung cancer. However, most of patients resist chemotherapy resulting in disease progressive and recurrence. Titin (TTN) mutation is proved as a beneficial role in lung squamous carcinoma (LUSC), but the predictive role on chemotherapy resistance of lung cancer is still limited and discussable.MethodsClinical information and related somatic mutation profiles were obtained from The Cancer Genome Atlas (TCGA) database and analyzed by R-Studio using R-package. Overall survival (OS) curve and the association between gene mutation and clinical features were determined by GraphPad 6.0 software.ResultsAvailable data including 563 lung adenocarcinoma (LUAD) and 505 LUSC subjects were included in this study. Among all patients, 205 out of 563 LUAD and 326 out of 505 LUSC patients displayed TTN gene mutation. When comparing the clinical features in TTN-mutated patients to patients without TTN mutation who received chemotherapy, the tumors were always located in the upper lung in LUAD patients with TTN mutation and most of TTN-mutated subjects were at low pathological stage, which was not observed in LUSC patients. However, patients with TTN-mutation, particularly missense mutation, had a higher chemosensitivity and longer OS period than that patients without TTN mutation in both LUAD and LUSC. Of note, LUAD and LUSC patients possessed favorable OS and better chemotherapy response benefiting from TTN/tumor protein 53 (TP53) double mutation compared to TTN and TP53 mutation alone, respectively. Additionally, TTN/TP53 double mutation-initiated high rate of chemotherapy response were largely concentrated within LUAD and LUSC patients whose anatomic neoplasm subdivision were located in the upper lung.ConclusionsCollectively, TTN/TP53 co-mutation is possibly served as an effective predictor for OS and chemotherapy response in lung cancer.

Validation of the 12-gene Predictive Signature for Adjuvant Chemotherapy Response in Lung Cancer.

Response to adjuvant chemotherapy after tumor resection varies widely among patients with non-small cell lung cancer (NSCLC); therefore, it is of clinical importance to prospectively predict who will benefit from adjuvant chemotherapy before starting the treatment. The goal of this study is to validate a 12-gene adjuvant chemotherapy predictive signature developed from a previous study using a clinical-grade assay. We developed a clinical-grade assay for formalin-fixed, paraffin-embedded (FFPE) samples using the NanoString nCounter platform to measure the mRNA expression of the previously published 12-gene set. The predictive performance was validated in a cohort of 207 patients with early-stage resected NSCLC with matched propensity score of adjuvant chemotherapy. The effects of adjuvant chemotherapy were significantly different in patients from the predicted adjuvant chemotherapy benefit group and those in the predicted adjuvant chemotherapy nonbenefit group (P = 0.0056 for interaction between predicted risk group and adjuvant chemotherapy). Specifically, in the predicted adjuvant chemotherapy benefit group, the patients receiving adjuvant chemotherapy had significant recurrence-free survival (RFS) benefit (HR = 0.34; P = 0.016; adjuvant chemotherapy vs. nonadjuvant chemotherapy), while in the predicted adjuvant chemotherapy nonbenefit group, the patients receiving adjuvant chemotherapy actually had worse RFS (HR = 1.86; P = 0.14; adjuvant chemotherapy vs. nonadjuvant chemotherapy) than those who did not receive adjuvant chemotherapy. This study validated that the 12-gene signature and the FFPE-based clinical assay predict that patients whose resected lung adenocarcinomas exhibit an adjuvant chemotherapy benefit gene expression pattern and who then receive adjuvant chemotherapy have significant survival advantage compared with patients whose tumors exhibit the benefit pattern but do not receive adjuvant chemotherapy.

Validation of the 12-Gene Predictive Signature for Adjuvant Chemotherapy Response in Lung Cancer

Validation of the 12-Gene Predictive Signature for Adjuvant Chemotherapy Response in Lung Cancer

Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo.

Caspase-2 is an atypical caspase that regulates apoptosis, cell cycle arrest and genome maintenance, although the mechanisms are not well understood. Caspase-2 has also been implicated in chemotherapy response in lung cancer, but this function has not been addressed in vivo. Here we show that Caspase-2 functions as a tumor suppressor in Kras-driven lung cancer in vivo. Loss of Caspase-2 leads to enhanced tumor proliferation and progression. Despite being more histologically advanced, Caspase-2-deficient tumors are sensitive to chemotherapy and exhibit a significant reduction in tumor volume following repeated treatment. However, Caspase-2-deficient tumors rapidly rebound from chemotherapy with enhanced proliferation, ultimately hindering long-term therapeutic benefit. In response to DNA damage, Caspase-2 cleaves and inhibits Mdm2 and thereby promotes the stability of the tumor-suppressor p53. Caspase-2 expression levels are significantly reduced in human lung tumors with wild-type p53, in agreement with the model whereby Caspase-2 functions through Mdm2/p53 regulation. Consistently, p53 target genes including p21, cyclin G1 and Msh2 are reduced in Caspase-2-deficient tumors. Finally, we show that phosphorylation of p53-induced protein with a death domain 1 leads to Caspase-2-mediated cleavage of Mdm2, directly impacting p53 levels, activity and chemotherapy response. Together, these studies elucidate a Caspase-2-p53 signaling network that impacts lung tumorigenesis and chemotherapy response in vivo.

Association ofHMGB1andHMGB2genetic polymorphisms with lung cancer chemotherapy response

The aim of the present study was to investigate the association of genetic polymorphisms in high mobility group box 1 and 2 (HMGB1 and HMGB2, respectively) with platinum-based chemotherapy responses in Chinese lung cancer patients. In total, 338 Chinese lung cancer patients (154 responders and 184 non-responders) were recruited to the study. All patients received at least two cycles of first-line platinum-based chemotherapy. Three tagging single nucleotide polymorphisms (SNPs) of HMGB1 and two tagging SNPs of HMGB2 were detected in patients. We found that rs1412125 and rs2249825 of HMGB1 were significantly associated with the platinum-based chemotherapy response in both recessive and genotypic models. In addition, rs1412125 showed significant association with platinum-based chemotherapy response for the subgroup of patients aged >55years in additive, recessive and genotypic models. No significant associations were detected between other SNPs and the platinum-based chemotherapy response. The HMGB1 SNPs (rs1412125 and rs2249825) were associated with platinum-based chemotherapy responses in Chinese lung cancer patients. In conclusion, HMGB1 SNPs may serve as potential biomarkers for predicting the efficacy of platinum-based chemotherapy.

The Association of Transporter Genes Polymorphisms and Lung Cancer Chemotherapy Response

Lung cancer is one of the most common cancers and is the leading cause of death worldwide. Platinum-based chemotherapy is the main treatment method in lung cancer patients. Our previous studies indicated that single nucleotide polymorphisms (SNPs) in some transporter genes played important role in platinum-based chemotherapy efficacy. The aim of this study was to investigate the association of SNPs in transporter genes and platinum-based chemotherapy efficacy. The main polymorphisms on transporters OCT2, LRP, AQP2, AQP9 and TMEM205 genes were genotyped in 338 lung cancer patients. The rs195854 in genotypic model, rs896412 in genotypic and recessive models for all subjects showed significant association with chemotherapy response. In stratification analysis, TMEM205 rs896412, OCT2 rs1869641 and rs195854, AQP9 rs1516400 and AQP2 rs7314734 showed significant relation to chemotherapy response. In conclusion, the genetic polymorphisms in OCT2, AQP2, AQP9 and TMEM205 may contribute to chemotherapy response in lung cancer patients.

A comprehensive study of polymorphisms in ABCB1, ABCC2 and ABCG2 and lung cancer chemotherapy response and prognosis

ATP-binding cassette (ABC) transporter expression and genetic heterogeneity have been implicated in response to anticancer therapy. This study characterized genetic variability of the ABCB1 (also known as MDR1), ABCC2 (MRP2) and ABCG2 (BCRP) genes, which are key players in the metabolism of many chemotherapeutic agents including those used in the treatment of lung cancer. We genotyped 53 polymorphisms in the candidate genes in genomic DNA samples of 171 cases of small cell lung carcinoma (SCLC) and 206 cases of non-small cell lung carcinoma (NSCLC), and studied their impact on early response to chemotherapy, progression-free survival and overall survival. SNP rs717620 in ABCC2 was moderately associated with a poor response to chemotherapy but strongly with shorter progression-free survival and overall survival in SCLC but not NSCLC patients, indicating that ABCC2 genetic variation is an important factor in SCLC survival after chemotherapy.

Molecular biomarkers for predicting chemotherapy response in lung cancer

Chemotherapy in non-small-cell lung cancer (NSCLC) has reached a plateau, with no evidence of substantial improvement in survival. However, recent advances in the management of lung cancer have paved the way for the optimization of treatment. Several lines of evidence indicate that multiple genetic disturbances found in human cancer cell lines and in the tumors of NSCLC patients have a role as predictive markers for response and survival with chemotherapy regimens now in use. This review highlights relevant translational research findings on potential predictive markers in lung cancer with therapeutic impact in both the near and distant future. The next step is to develop clinical trials that will prospectively validate the benefits of customizing chemotherapy, which should translate into an improvement in outcome in NSCLC patients.

Single nucleotide polymorphisms in matrix metalloproteinase genes and lung cancer chemotherapy response and prognosis

The prognosis for lung cancer patients treated with chemotherapy is poor. Single nucleotide polymorphisms (SNPs) in matrix metalloproteinase (MMP) genes could influence treatment outcome by altering apoptotic pathways. Eight SNPs with known or suspected phenotypic effect in six genes (MMP1, MMP2, MMP3, MMP7, MMP9 and MMP12) were investigated. For 349 Caucasian patients with primary lung cancer, receiving first-line chemotherapy, three different endpoints were analysed: response after the second cycle, progression free survival (PFS) and overall survival (OS). The prognostic value of the SNPs was analysed using multiple logistic regression for all patients and histology-, stage- and treatment-specific subgroups. Hazard ratio estimates for PFS and OS were calculated using Cox regression methods. None of the investigated polymorphisms modified response significantly in the whole patient population. However, tumour stage IIIB variant allele carriers of MMP2 C-735T showed a significantly worse response. PFS was significantly prolonged in MMP1 G-1607GG variant allele carriers and OS in small cell lung cancer patients carrying the MMP12 A-82G variant allele. In conclusion, this study identified SNPs in MMP1, MMP2, MMP7 and MMP12 for further investigation as possible predictors of chemotherapy outcome in lung cancer patients.

Targeted reduction of KLF6-SV1 restores chemotherapy sensitivity in resistant lung adenocarcinoma

Kruppel-like factor 6 splice variant 1 (KLF6-SV1) is an oncogenic splice variant of the KLF6 tumor suppressor gene that is specifically overexpressed in a number of human cancers. Previously, we have demonstrated that increased expression of KLF6-SV1 is associated with decreased survival in lung adenocarcinoma patient samples and that targeted reduction of KLF6-SV1 using siRNA induced apoptosis both alone and in combination with the chemotherapeutic drug cisplatin. Here, we demonstrate that chemoresistant lung cancer cells express increased levels of KLF6-SV1. Furthermore, targeted reduction of KLF6-SV1 using RNA interference restores chemotherapy sensitivity to lung cancer cells both in culture and in vivo through induction of apoptosis. Conversely, overexpression of KLF6-SV1 resulted in a marked reduction in chemotherapy sensitivity in a tumor xenograft model. Combined, these findings highlight a functional role for the KLF6-SV1 splice variant in the regulation of chemotherapy response in lung cancer and could provide novel insight into lung cancer therapy.

Association of eIF3 p170 expression with chemotherapy response of lung cancer and its effects on cisplatin sensitivity in lung carcinoma cells

Association of eIF3 p170 expression with chemotherapy response of lung cancer and its effects on cisplatin sensitivity in lung carcinoma cells

Usefulness of chest single photon emission computed tomography with technetium-99m methoxyisobutylisonitrile to predict taxol based chemotherapy response in advanced non-small cell lung cancer.

In vitro studies have shown that technetium-99m methoxyisobutylisonitrile (Tc-99m MIBI) is a transport substrate for the P-glycoprotein (Pgp) pump. Therefore, Tc-99m MIBI uptake of tumors can be used to predict chemotherapy response in lung cancers. However, whether lung resistance-related protein (LRP) expression affects tumor accumulation and efflux of Tc-99m MIBI in lung cancers is not known. Our aim was to use Tc-99m MIBI uptake of tumors to predict Taxol based chemotherapy response of advanced non-small cell lung cancer (NSCLC) and to compare Pgp or LRP expression. Before chemotherapy with Taxol, 30 patients with stage IIIb or IV NSCLC were enrolled in this study. Chemotherapy response was evaluated in the third month after completion of treatment by clinical and radiological methods. No significant differences were found for other prognostic factors (age, sex, body weight loss, performance status, tumor cell type, and tumor stage) between the 15 patients with good response and the other 15 patients with poor response. Early chest single photon emission computed tomography (SPECT) was performed 10 min after intravenous injection of Tc-99m MIBI. Early tumor-to-normal lung (T/L) uptake ratios were calculated quantitatively on Tc-99m MIBI chest SPECT images. Immunohistochemical analyses were performed on multiple nonconsecutive sections of the biopsy specimens to determine Pgp and LRP expressions. The T/L uptake ratios on early Tc-99m MIBI chest SPECT images of 15 patients with good response were significantly higher than those of the other 15 patients with poor response. Significantly higher T/L uptake ratios were found in patients with negative than positive Pgp expression (p<0.05). However, no significant differences of T/L uptake ratios were found between patients with negative and positive LRP expressions (p>0.05). We concluded that Tc-99m MIBI chest SPECT could accurately predict Taxol base chemotherapy response of patients with advanced NSCLC. In addition, The Tc-99m MIBI tumor uptake was related to Pgp but not LPR expression in NSCLC.

Using technetium-99m tetrofosmin chest imaging to predict taxol-based chemotherapy response in non-small cell lung cancer but not related to lung resistance protein expression.

In vitro studies have shown that technetium-99m tetrofosmin (Tc-99m TF) is a transport substrate for the P-glycoprotein (Pgp) pump. Therefore, Tc-99m TF uptake of tumors can be used to predict chemotherapy response in lung cancers. However, whether lung resistance-related protein (LRP) expression affects tumor accumulation and efflux of Tc-99m TF in lung cancers is not known. Our aim was to use Tc-99m TF uptake of tumors to predict paclitaxel-based chemotherapy response of non-small cell lung cancer (NSCLC) and to compare Pgp or LRP expression. Twenty patients with advanced NSCLC received Tc-99m TF chest images before Taxol-based chemotherapy was used in this study. The chemotherapy response was evaluated by clinical and radiological methods in the third month after completion of treatment. No significant differences of prognostic factors (age, sex, body weight loss, performance status, tumor size, tumor stage, and tumor cell type) were found between the patients with good and those with poor responses. Early and delayed tumor/normal lung (T/L) uptake ratios were calculated on Tc-99m TF chest images. Immunohistochemical analyses were performed on multiple nonconsecutive sections of the biopsy specimens to detect Pgp and LPR expressions. The early and delayed T/L uptake ratios of 10 patients with good response were significantly higher than those of the other 10 patients with poor response. Significantly higher early and delayed T/L uptake ratios were found in patients with negative than those with positive Pgp expression ( p < 0.05). However, no significant differences of early and delayed T/L uptake ratios were found between patients with negative and positive LRP expressions ( p > 0.05). We found that Tc-99m TF imaging could accurately predict Taxol-base chemotherapy response. In addition, the Tc-99m TF tumor uptake was related to Pgp but not LPR expression in NSCLC.

The role of Tc-99m sestamibi imaging in predicting clinical response to chemotherapy in lung cancer.

Multidrug resistance (MDR) is a major problem in lung cancer. Tc-99m methoxyisobutyl isonitrile (MIBI) has been demonstrated to be a non-invasive marker to diagnose MDRI related P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) expression in various solid tumors. The aim of this study was to evaluate the relationship between the degree of Tc-99m MIBI uptake and its retention on delayed images and the response to chemotherapy in lung cancer. Twenty-three patients (1 woman and 22 men, age range 40-67 years) with lung cancer (9 small cell and 14 non-small cell) were examined with Tc-99m MIBI imaging before chemotherapy. After i.v. administration of 740 MBq Tc-99m MIBI, planar and SPECT imaging at 30 minutes and 2 hours was performed. Tumor to normal lung uptake ratio (T/N) and percent retention were measured. Response to chemotherapy was evaluated according to follow-up CT and grouped as complete responders (CR), partial responders (PR) and non-responders (NR). Clinical follow-up and CT evaluation revealed that 12 patients had partial remission, 4 patients had complete remission and 7 patients had no-remission after chemotherapy. Statistically, there was no significant correlation between early (30 min), delayed (2 hr) T/N ratios and percent retention of Tc-99m MIBI with chemotherapeutic response of the lung cancer among the three groups (p > 0.05). Results of the current study imply that Tc-99m MIBI uptake and the retention index may not correlate with chemotherapy response in lung cancer, so that the accuracy of this method needs to be verified in a larger series with additional investigation at the molecular level.