ERH Interacts With EIF2α and Regulates the EIF2α/ATF4/CHOP Pathway in Bladder Cancer Cells

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.

The current treatment paradigm for muscle-invasive bladder cancer (MIBC) consists of cisplatin-based neoadjuvant chemotherapy followed by local definitive therapy, or local definitive therapy alone for cisplatin-ineligible patients. Given that MIBC has a high propensity for distant relapse and is a chemotherapy-sensitive disease, under-utilization of chemotherapy is associated with suboptimal cure rates. Cisplatin eligibility criteria are defined for patients with metastatic bladder cancer by the Galsky criteria, which include creatinine clearance ≥60 ml/min. However, consensus is still lacking regarding cisplatin eligibility criteria in the neoadjuvant, curative MIBC setting, which continues to represent a substantial barrier to the standardization of patient care and clinical trial design. Jiang and colleagues accordingly suggest an algorithm for assessing cisplatin eligibility in patients with MIBC. Instead of relying on an absolute renal function threshold, their algorithm emphasizes a multidisciplinary and patient-centred approach. They also propose mitigation strategies to minimize the risk of cisplatin-induced nephrotoxicity in selected patients with impaired renal function. This new framework is aimed at reducing the inappropriate exclusion of some patients from cisplatin-based neoadjuvant chemotherapy (which leads to under-treatment) and harmonizing clinical trial design, which could lead to improved overall outcomes in patients with MIBC.

Cancers with Ras mutations represent a major therapeutic problem. Recent RNAi screens have uncovered multiple nononcogene addiction pathways that are necessary for the survival of Ras mutant cells. Here, we identify the evolutionarily conserved gene enhancer of rudimentary homolog (ERH), in which depletion causes greater toxicity in cancer cells with mutations in the small GTPase KRAS compared with KRAS WT cells. ERH interacts with the spliceosome protein SNRPD3 and is required for the mRNA splicing of the mitotic motor protein CENP-E. Loss of ERH leads to loss of CENP-E and consequently, chromosome congression defects. Gene expression profiling indicates that ERH is required for the expression of multiple cell cycle genes, and the gene expression signature resulting from ERH down-regulation inversely correlates with KRAS signatures. Clinically, tumor ERH expression is inversely associated with survival of colorectal cancer patients whose tumors harbor KRAS mutations. Together, these findings identify a role of ERH in mRNA splicing and mitosis, and they provide evidence that KRAS mutant cancer cells are dependent on ERH for their survival.