Some Aggressive Cancers May Respond to Anti-Inflammatory Drugs

“New research raises the prospect that some cancer patients with aggressive tumors may benefit from a class of anti-inflammatory drugs used to treat rheumatoid arthritis.

“Studying triple-negative breast cancer, researchers at Washington University School of Medicine in St. Louis found that some aggressive tumors rely on an antiviral pathway that appears to drive inflammation, widely recognized for roles in cancer, rheumatoid arthritis and other inflammatory diseases.

“The tumors that activate this particular antiviral pathway always have dysfunctional forms of the proteins p53 and ARF, both encoded by genes known for being highly mutated in various cancers. The investigators found that the two genes compensate for each other. If both are mutated, the tumors that form are more aggressive than if only one of these genes is lost.

“When both genes are lost and the antiviral pathway is activated, patients may benefit from a class of anti-inflammatory drugs called JAK inhibitors, currently prescribed for rheumatoid arthritis.”

Editor’s note: Recent research shows that drugs known as JAK inhibitors, often prescribed for arthritis, might also help fight certain types of breast cancer. Specifically, JAK inhibitors might benefit patients with triple-negative breast cancer whose tumors have mutated forms of the proteins p53 and ARF. The researchers are working with specialists to identify patients with those mutations who might benefit from JAK inhibitors.


Antioxidants May Actually Speed Lung Cancer Growth in Some Cases

Antioxidants are chemicals that neutralize particles called free radicals that can damage DNA. Preventing such damage may help lower cancer risk for some people. However, tumors themselves can contain high levels of free radicals; by eliminating these free radicals, antioxidants may help cancer cells grow. In a laboratory, lung cancer cells treated with the antioxidants vitamin E and acetylcysteine (ACC) multiplied faster than untreated cells. Vitamin E and ACC also increased tumor growth and decreased survival time in mice with lung cancer. The so-called ‘tumor suppressor’ protein p53 can sense certain free radicals to detect cells with DNA damage and stop their growth. Antioxidants may interfere with this cancer-suppressing mechanism by reducing free radical levels. Taking antioxidants may therefore not be recommended for lung cancer patients and smokers.


New Targeted Drugs May Offer Treatment for KRAS-Mutant Lung Cancer

Abnormalities in the KRAS gene are the most common mutations in lung cancer, especially in lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC). However, no effective targeted therapy directed at KRAS has been found. Instead, researchers have begun to focus on blocking molecules “downstream” in the chain of chemical reactions through which KRAS affects the cell. Two such molecules are TBK1 and MEK. A recent study found that the drug CYT387 blocks TBK1. CYT387 reduced tumor growth in mice with KRAS-mutant lung adenocarcinoma. Also in mice, CYT387 and the MEK inhibitor AZD6244, given together, shrank aggressive lung tumors with mutations in both the KRAS and the TP53 gene. Researchers now hope to investigate the two drugs in people.


Lung Cancer Is Associated With 'Aged' Immune Cells

As cells age, they eventually stop multiplying, a state known as ‘senescence.’ Accumulation of senescent cells is thought to contribute to the symptoms of aging. A study examining T cells, a type of immune cell, found that lung cancer patients had more senescent T cells, much like healthy patients during aging. T cells from both aged individuals and lung cancer patients had increased levels of senescence-promoting proteins and lower levels of proteins that promote continued cell multiplication. This ‘artificial aging’ of immune cells may weaken the immune system’s ability to attack the cancer. The study’s authors suggest that treatments to ward off senescence in immune cells may in the future help avoid the weakening of the immune system seen in cancer and other aging-related diseases.


Molecular Cell – HDAC5, a Key Component in Temporal Regulation of p53-Mediated Transactivation in Response to Genotoxic Stress

“Despite being one of the most well-studied transcription factors, the temporal regulation of p53-mediated transcription is not very well understood. Recent data suggest that target specificity of p53-mediated transactivation is achieved by posttranslational modifications of p53. K120 acetylation is a modification critical for recruitment of p53 to proapoptotic targets. Our data reveal that histone deacetylase 5 (HDAC5) binds to p53 and abrogates K120 acetylation, resulting in preferential recruitment of p53 to proarrest and antioxidant targets at early phases of stress. However, upon prolonged genotoxic stress, HDAC5 undergoes nuclear export. Concomitantly, p53 is acetylated at the K120 residue and selectively transactivates proapoptotic target genes, leading to onset of apoptosis. Furthermore, upon genotoxic stress in mice where HDAC5 expression is downregulated, the onset of apoptosis is accelerated in the highly vulnerable tissues. These findings suggest that HDAC5 is a key determinant of p53-mediated cell fate decisions in response to genotoxic stress.”


Molecular Cell – HDAC5, a Key Component in Temporal Regulation of p53-Mediated Transactivation in Response to Genotoxic Stress

“Despite being one of the most well-studied transcription factors, the temporal regulation of p53-mediated transcription is not very well understood. Recent data suggest that target specificity of p53-mediated transactivation is achieved by posttranslational modifications of p53. K120 acetylation is a modification critical for recruitment of p53 to proapoptotic targets. Our data reveal that histone deacetylase 5 (HDAC5) binds to p53 and abrogates K120 acetylation, resulting in preferential recruitment of p53 to proarrest and antioxidant targets at early phases of stress. However, upon prolonged genotoxic stress, HDAC5 undergoes nuclear export. Concomitantly, p53 is acetylated at the K120 residue and selectively transactivates proapoptotic target genes, leading to onset of apoptosis. Furthermore, upon genotoxic stress in mice where HDAC5 expression is downregulated, the onset of apoptosis is accelerated in the highly vulnerable tissues. These findings suggest that HDAC5 is a key determinant of p53-mediated cell fate decisions in response to genotoxic stress.”


Molecular Cell – HDAC5, a Key Component in Temporal Regulation of p53-Mediated Transactivation in Response to Genotoxic Stress

“Despite being one of the most well-studied transcription factors, the temporal regulation of p53-mediated transcription is not very well understood. Recent data suggest that target specificity of p53-mediated transactivation is achieved by posttranslational modifications of p53. K120 acetylation is a modification critical for recruitment of p53 to proapoptotic targets. Our data reveal that histone deacetylase 5 (HDAC5) binds to p53 and abrogates K120 acetylation, resulting in preferential recruitment of p53 to proarrest and antioxidant targets at early phases of stress. However, upon prolonged genotoxic stress, HDAC5 undergoes nuclear export. Concomitantly, p53 is acetylated at the K120 residue and selectively transactivates proapoptotic target genes, leading to onset of apoptosis. Furthermore, upon genotoxic stress in mice where HDAC5 expression is downregulated, the onset of apoptosis is accelerated in the highly vulnerable tissues. These findings suggest that HDAC5 is a key determinant of p53-mediated cell fate decisions in response to genotoxic stress.”


Runx3 Inactivation Is a Crucial Early Event in the Development of Lung Adenocarcinoma

“A functional genetic screen of a fly mutant library and molecular analysis in cultured cell lines revealed that Runx3 forms a complex with BRD2 in a K-Ras-dependent manner in the early phase of the cell cycle; this complex induces expression of p14ARF/p19Arf and p21WAF/CIP. When K-Ras was constitutively activated, the Runx3-BRD2 complex was stably maintained and expression of both p14ARF and p21WAF/CIP was prolonged. These results provide a missing link between oncogenic K-Ras and the p14ARF-p53 pathway, and may explain how cells defend against oncogenic K-Ras.”


YEATS4 is a Novel Oncogene Amplified in Non-Small Cell Lung Cancer that Regulates the p53 Pathway

We conducted an integrative analysis of gene expression and copy number in 261 non-small cell lung cancers (NSCLC) relative to matched normal tissues to define novel candidate oncogenes, identifying 12q13-15 and more specifically the YEATS4 gene as amplified and overexpressed in ~20% of the NSCLC cases examined.