John Minna | University of Texas Southwestern Medical Center at Dallas (original) (raw)
Papers by John Minna
Cancer research, 2001
A cDNA clone encoding human SRBC [serum deprivation response factor (sdr)-related gene product th... more A cDNA clone encoding human SRBC [serum deprivation response factor (sdr)-related gene product that binds to c-kinase] was isolated in a yeast two-hybrid screening, with amino acids 1-304 of BRCA1 as the probe. The human SRBC gene (hSRBC) was mapped to chromosome region 11p15.5-p15.4, close to marker D11S1323, at which frequent loss of heterozygosity (LOH) has been observed in sporadic breast, lung, ovarian, and other types of adult cancers as well as childhood tumors. hSRBC-coding region mutations including frame shift and truncation mutations were detected in a few ovarian and lung cancer cell lines. More significantly, the expression of hSRBC protein was down-regulated in a large fraction [30 (70%) of 43] of breast, lung, and ovarian cancer cell lines, whereas strong expression of hSRBC protein was detected in normal mammary and lung epithelial cells. The down-regulation of hSRBC expression in cancer cells was associated with hypermethylation of CpG dinucleotides in its promoter ...
Neoplasia (New York, N.Y.), Aug 1, 2018
Standard and targeted cancer therapies for late-stage cancer patients almost universally fail due... more Standard and targeted cancer therapies for late-stage cancer patients almost universally fail due to tumor heterogeneity/plasticity and intrinsic or acquired drug resistance. We used the telomerase substrate nucleoside precursor, 6-thio-2'-deoxyguanosine (6-thio-dG), to target telomerase-expressing non-small cell lung cancer cells resistant to EGFR-inhibitors and commonly used chemotherapy combinations. Colony formation assays, human xenografts as well as syngeneic and genetically engineered immune competent mouse models of lung cancer were used to test the effect of 6-thio-dG on targeted therapy- and chemotherapy-resistant lung cancer human cells and mouse models. We observed that erlotinib-, paclitaxel/carboplatin-, and gemcitabine/cisplatin-resistant cells were highly sensitive to 6-thio-dG in cell culture and in mouse models. 6-thio-dG, with a known mechanism of action, is a potential novel therapeutic approach to prolong disease control of therapy-resistant lung cancer pati...
Oncotarget, Jan 3, 2018
LMO1 encodes a protein containing a cysteine-rich LIM domain involved in protein-protein interact... more LMO1 encodes a protein containing a cysteine-rich LIM domain involved in protein-protein interactions. Recent studies have shown that LMO1 functions as an oncogene in several cancer types, including non-small cell lung cancer (NSCLC). However, the function of LMO1 in other histological subtypes of lung cancer, such as small cell lung cancer (SCLC), was not investigated. In analyzing the expression of LMO1 across a panel of lung cell lines, we found that LMO1 expression levels were significantly and dramatically higher in SCLC cells, an aggressive neuroendocrine subtype of lung cancer, relative to NSCLC and normal lung cells. In NSCLC cells, LMO1 mRNA levels were significantly correlated with expression of neuroendocrine differentiation markers. Our investigations indicated that LMO1 had the general property of promoting cell proliferation in lung cancer cells representing different histological subtypes, suggesting a general oncogenic function of LMO1 in lung cancer. In investigatin...
Translational oncology, 2018
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma, designated as a recalcit... more Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma, designated as a recalcitrant cancer by the National Cancer Institute, in urgent need of new rational therapeutic targets. Previous studies have determined that the basic helix-loop-helix transcription factor achaete-scute homolog 1 (ASCL1) is essential for the survival and progression of a fraction of pulmonary neuroendocrine cancer cells, which include both SCLC and a subset of non-SCLC. Previously, to understand how ASCL1 initiates tumorigenesis in pulmonary neuroendocrine cancer and identify the transcriptional targets of ASCL1, whole-genome RNA-sequencing analysis combined with chromatin immunoprecipitation-sequencing was performed with a series of lung cancer cell lines. From this analysis, we discovered that the gene SCNN1A, which encodes the alpha subunit of the epithelial sodium channel (αENaC), is highly correlated with ASCL1 expression in SCLC. The product of the SCNN1A gene ENaC can be pharmacologica...
Cell reports, May 23, 2017
Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemothe... more Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemotherapy, many relapse, developing drug resistance. We established preclinical taxane-platin-chemoresistance models and identified a 35-gene resistance signature, which was associated with poor recurrence-free survival in neoadjuvant-treated NSCLC patients and included upregulation of the JumonjiC lysine demethylase KDM3B. In fact, multi-drug-resistant cells progressively increased the expression of many JumonjiC demethylases, had altered histone methylation, and, importantly, showed hypersensitivity to JumonjiC inhibitors in vitro and in vivo. Increasing taxane-platin resistance in progressive cell line series was accompanied by progressive sensitization to JIB-04 and GSK-J4. These JumonjiC inhibitors partly reversed deregulated transcriptional programs, prevented the emergence of drug-tolerant colonies from chemo-naive cells, and synergized with standard chemotherapy in vitro and in vivo. ...
Oncotarget, Jan 29, 2016
The "conditionally reprogrammed cells" (CRC) method, using a Rho kinase inhibitor and i... more The "conditionally reprogrammed cells" (CRC) method, using a Rho kinase inhibitor and irradiated mouse fibroblast cells has been described for the efficient growth of cells from malignant and non-malignant samples from primary tumor and non-malignant sites. Using the CRC method, four institutions independently cultured tumor tissues from 48 non-small cell lung cancers (NSCLC, mostly from primary resected tumors) and 22 non-malignant lungs. We found that epithelial cells could be cultured from tumor and non-malignant lung. However, epithelial cells cultured from tumors had features of non-malignant respiratory epithelial cells which include: 1) among 22 mutations found in the original tumors only two mutations were found in the CRC cultures with reduced frequency (31% to 13% and 92% to 15% from original tumor and CRC culture respectively); 2) copy number variation was analyzed in 9 tumor and their CRC cultures and only diploid patterns were found in CRC cultures; 3) mRNA ex...
Lung cancer is the leading cause of cancer death in the United States and the world. The most eff... more Lung cancer is the leading cause of cancer death in the United States and the world. The most effective therapy is surgical resection, but lung cancer recurs in approximately 50% of patients, most commonly as metastatic disease. This suggests that micrometastatic disease is often already present at the time of surgery, but below current levels of clinical detection. This is consistent with the reports of circulating tumor cells (CTCs) in patients with Stage I non-small cell lung cancer (NSCLC). Although metastatic behavior is often considered a late event, these clinical findings suggest that the metastatic process is also operative early in the pathogenesis of the disease. These v The dissertation of Paul Carmelo Pagano is approved.
Cancer, 2014
(1) PURPOSE-The advent of effective targeted therapy in BRAF V600E mutant lung adenocarcinomas ne... more (1) PURPOSE-The advent of effective targeted therapy in BRAF V600E mutant lung adenocarcinomas necessitates further exploration of the unique clinical features and behavior of advanced stage BRAF mutant lung adenocarcinomas. (2) PATIENTS AND METHODS-We reviewed data from patients with advanced lung adenocarcinomas enrolled in the Lung Cancer Mutation Consortium whose tumors underwent testing for mutations in EGFR, KRAS, HER2, AKT1, BRAF, MEK1, NRAS, PIK3CA, ALK translocations, and MET amplification. (3) RESULTS-Twenty-one BRAF mutations were identified in 951 patients with adenocarcinomas (2.2%: 95% CI 1.4 to 3.4%); 17 (81%: 95% CI 60 to 92%) were BRAF V600E and 4 were non-BRAF V600E mutations. Among the 733 cases tested for all 10 genes, BRAF mutations were more likely to occur in current or former smokers than most other genotypic abnormalities
Journal of Clinical Investigation, 1989
Cancer Prevention Research, 2014
Cancer Prevention Research, 2008
Seminars in Radiation …, 2010
Molecular Cancer …, 2009
FUS1, also known as tumor suppressor candidate 2 (TUSC2), is a tumor suppressor gene located on h... more FUS1, also known as tumor suppressor candidate 2 (TUSC2), is a tumor suppressor gene located on human chromosome 3p21.3, a region in which deficient gene expression is frequently seen in lung cancer (1). The tumor suppressor function of Fus1 has been shown in studies ...
Recent studies have established that amplification of the MET proto-oncogene can cause resistance... more Recent studies have established that amplification of the MET proto-oncogene can cause resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) cell lines with EGFR-activating mutations. The role of nonamplified MET in EGFR-dependent signaling before TKI resistance, however, is not well understood. Using NSCLC cell lines and transgenic models, we demonstrate here that EGFR activation by either mutation or ligand binding increases MET gene expression and protein levels. Our analysis of 202 NSCLC patient specimens was consistent with these observations: levels of MET were significantly higher in NSCLC with EGFR mutations than in NSCLC with wild-type EGFR. EGFR regulation of MET levels in cell lines occurred through the hypoxiainducible factor (HIF)-1a pathway in a hypoxia-independent manner. This regulation was lost, however, after MET gene amplification or overexpression of a constitutively active form of HIF-1a. EGFR-and hypoxia-induced invasiveness of NSCLC cells, but not cell survival, were found to be MET dependent. These findings establish that, absent MET amplification, EGFR signaling can regulate MET levels through HIF-1a and that MET is a key downstream mediator of EGFR-induced invasiveness in EGFR-dependent NSCLC cells.
Clinical cancer …, 2006
Purpose: Recognition that the epidermal growth factor receptor (EGFR) was a therapeutic target in... more Purpose: Recognition that the epidermal growth factor receptor (EGFR) was a therapeutic target in nonsmall cell lung cancer (NSCLC) and other cancers led to development of the small-molecule receptor tyrosine kinase inhibitors gefitinib and erlotinib. Clinical trials established that ...
Cancer research, 2001
A cDNA clone encoding human SRBC [serum deprivation response factor (sdr)-related gene product th... more A cDNA clone encoding human SRBC [serum deprivation response factor (sdr)-related gene product that binds to c-kinase] was isolated in a yeast two-hybrid screening, with amino acids 1-304 of BRCA1 as the probe. The human SRBC gene (hSRBC) was mapped to chromosome region 11p15.5-p15.4, close to marker D11S1323, at which frequent loss of heterozygosity (LOH) has been observed in sporadic breast, lung, ovarian, and other types of adult cancers as well as childhood tumors. hSRBC-coding region mutations including frame shift and truncation mutations were detected in a few ovarian and lung cancer cell lines. More significantly, the expression of hSRBC protein was down-regulated in a large fraction [30 (70%) of 43] of breast, lung, and ovarian cancer cell lines, whereas strong expression of hSRBC protein was detected in normal mammary and lung epithelial cells. The down-regulation of hSRBC expression in cancer cells was associated with hypermethylation of CpG dinucleotides in its promoter ...
Neoplasia (New York, N.Y.), Aug 1, 2018
Standard and targeted cancer therapies for late-stage cancer patients almost universally fail due... more Standard and targeted cancer therapies for late-stage cancer patients almost universally fail due to tumor heterogeneity/plasticity and intrinsic or acquired drug resistance. We used the telomerase substrate nucleoside precursor, 6-thio-2'-deoxyguanosine (6-thio-dG), to target telomerase-expressing non-small cell lung cancer cells resistant to EGFR-inhibitors and commonly used chemotherapy combinations. Colony formation assays, human xenografts as well as syngeneic and genetically engineered immune competent mouse models of lung cancer were used to test the effect of 6-thio-dG on targeted therapy- and chemotherapy-resistant lung cancer human cells and mouse models. We observed that erlotinib-, paclitaxel/carboplatin-, and gemcitabine/cisplatin-resistant cells were highly sensitive to 6-thio-dG in cell culture and in mouse models. 6-thio-dG, with a known mechanism of action, is a potential novel therapeutic approach to prolong disease control of therapy-resistant lung cancer pati...
Oncotarget, Jan 3, 2018
LMO1 encodes a protein containing a cysteine-rich LIM domain involved in protein-protein interact... more LMO1 encodes a protein containing a cysteine-rich LIM domain involved in protein-protein interactions. Recent studies have shown that LMO1 functions as an oncogene in several cancer types, including non-small cell lung cancer (NSCLC). However, the function of LMO1 in other histological subtypes of lung cancer, such as small cell lung cancer (SCLC), was not investigated. In analyzing the expression of LMO1 across a panel of lung cell lines, we found that LMO1 expression levels were significantly and dramatically higher in SCLC cells, an aggressive neuroendocrine subtype of lung cancer, relative to NSCLC and normal lung cells. In NSCLC cells, LMO1 mRNA levels were significantly correlated with expression of neuroendocrine differentiation markers. Our investigations indicated that LMO1 had the general property of promoting cell proliferation in lung cancer cells representing different histological subtypes, suggesting a general oncogenic function of LMO1 in lung cancer. In investigatin...
Translational oncology, 2018
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma, designated as a recalcit... more Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma, designated as a recalcitrant cancer by the National Cancer Institute, in urgent need of new rational therapeutic targets. Previous studies have determined that the basic helix-loop-helix transcription factor achaete-scute homolog 1 (ASCL1) is essential for the survival and progression of a fraction of pulmonary neuroendocrine cancer cells, which include both SCLC and a subset of non-SCLC. Previously, to understand how ASCL1 initiates tumorigenesis in pulmonary neuroendocrine cancer and identify the transcriptional targets of ASCL1, whole-genome RNA-sequencing analysis combined with chromatin immunoprecipitation-sequencing was performed with a series of lung cancer cell lines. From this analysis, we discovered that the gene SCNN1A, which encodes the alpha subunit of the epithelial sodium channel (αENaC), is highly correlated with ASCL1 expression in SCLC. The product of the SCNN1A gene ENaC can be pharmacologica...
Cell reports, May 23, 2017
Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemothe... more Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemotherapy, many relapse, developing drug resistance. We established preclinical taxane-platin-chemoresistance models and identified a 35-gene resistance signature, which was associated with poor recurrence-free survival in neoadjuvant-treated NSCLC patients and included upregulation of the JumonjiC lysine demethylase KDM3B. In fact, multi-drug-resistant cells progressively increased the expression of many JumonjiC demethylases, had altered histone methylation, and, importantly, showed hypersensitivity to JumonjiC inhibitors in vitro and in vivo. Increasing taxane-platin resistance in progressive cell line series was accompanied by progressive sensitization to JIB-04 and GSK-J4. These JumonjiC inhibitors partly reversed deregulated transcriptional programs, prevented the emergence of drug-tolerant colonies from chemo-naive cells, and synergized with standard chemotherapy in vitro and in vivo. ...
Oncotarget, Jan 29, 2016
The "conditionally reprogrammed cells" (CRC) method, using a Rho kinase inhibitor and i... more The "conditionally reprogrammed cells" (CRC) method, using a Rho kinase inhibitor and irradiated mouse fibroblast cells has been described for the efficient growth of cells from malignant and non-malignant samples from primary tumor and non-malignant sites. Using the CRC method, four institutions independently cultured tumor tissues from 48 non-small cell lung cancers (NSCLC, mostly from primary resected tumors) and 22 non-malignant lungs. We found that epithelial cells could be cultured from tumor and non-malignant lung. However, epithelial cells cultured from tumors had features of non-malignant respiratory epithelial cells which include: 1) among 22 mutations found in the original tumors only two mutations were found in the CRC cultures with reduced frequency (31% to 13% and 92% to 15% from original tumor and CRC culture respectively); 2) copy number variation was analyzed in 9 tumor and their CRC cultures and only diploid patterns were found in CRC cultures; 3) mRNA ex...
Lung cancer is the leading cause of cancer death in the United States and the world. The most eff... more Lung cancer is the leading cause of cancer death in the United States and the world. The most effective therapy is surgical resection, but lung cancer recurs in approximately 50% of patients, most commonly as metastatic disease. This suggests that micrometastatic disease is often already present at the time of surgery, but below current levels of clinical detection. This is consistent with the reports of circulating tumor cells (CTCs) in patients with Stage I non-small cell lung cancer (NSCLC). Although metastatic behavior is often considered a late event, these clinical findings suggest that the metastatic process is also operative early in the pathogenesis of the disease. These v The dissertation of Paul Carmelo Pagano is approved.
Cancer, 2014
(1) PURPOSE-The advent of effective targeted therapy in BRAF V600E mutant lung adenocarcinomas ne... more (1) PURPOSE-The advent of effective targeted therapy in BRAF V600E mutant lung adenocarcinomas necessitates further exploration of the unique clinical features and behavior of advanced stage BRAF mutant lung adenocarcinomas. (2) PATIENTS AND METHODS-We reviewed data from patients with advanced lung adenocarcinomas enrolled in the Lung Cancer Mutation Consortium whose tumors underwent testing for mutations in EGFR, KRAS, HER2, AKT1, BRAF, MEK1, NRAS, PIK3CA, ALK translocations, and MET amplification. (3) RESULTS-Twenty-one BRAF mutations were identified in 951 patients with adenocarcinomas (2.2%: 95% CI 1.4 to 3.4%); 17 (81%: 95% CI 60 to 92%) were BRAF V600E and 4 were non-BRAF V600E mutations. Among the 733 cases tested for all 10 genes, BRAF mutations were more likely to occur in current or former smokers than most other genotypic abnormalities
Journal of Clinical Investigation, 1989
Cancer Prevention Research, 2014
Cancer Prevention Research, 2008
Seminars in Radiation …, 2010
Molecular Cancer …, 2009
FUS1, also known as tumor suppressor candidate 2 (TUSC2), is a tumor suppressor gene located on h... more FUS1, also known as tumor suppressor candidate 2 (TUSC2), is a tumor suppressor gene located on human chromosome 3p21.3, a region in which deficient gene expression is frequently seen in lung cancer (1). The tumor suppressor function of Fus1 has been shown in studies ...
Recent studies have established that amplification of the MET proto-oncogene can cause resistance... more Recent studies have established that amplification of the MET proto-oncogene can cause resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) cell lines with EGFR-activating mutations. The role of nonamplified MET in EGFR-dependent signaling before TKI resistance, however, is not well understood. Using NSCLC cell lines and transgenic models, we demonstrate here that EGFR activation by either mutation or ligand binding increases MET gene expression and protein levels. Our analysis of 202 NSCLC patient specimens was consistent with these observations: levels of MET were significantly higher in NSCLC with EGFR mutations than in NSCLC with wild-type EGFR. EGFR regulation of MET levels in cell lines occurred through the hypoxiainducible factor (HIF)-1a pathway in a hypoxia-independent manner. This regulation was lost, however, after MET gene amplification or overexpression of a constitutively active form of HIF-1a. EGFR-and hypoxia-induced invasiveness of NSCLC cells, but not cell survival, were found to be MET dependent. These findings establish that, absent MET amplification, EGFR signaling can regulate MET levels through HIF-1a and that MET is a key downstream mediator of EGFR-induced invasiveness in EGFR-dependent NSCLC cells.
Clinical cancer …, 2006
Purpose: Recognition that the epidermal growth factor receptor (EGFR) was a therapeutic target in... more Purpose: Recognition that the epidermal growth factor receptor (EGFR) was a therapeutic target in nonsmall cell lung cancer (NSCLC) and other cancers led to development of the small-molecule receptor tyrosine kinase inhibitors gefitinib and erlotinib. Clinical trials established that ...