SummaryNF-κB transcription factors function as crucial regulators of inflammatory and immune responses as well as cell survival 1 . They have also been implicated in cellular transformation and tumorigenesis [2][3][4][5][6] . However, despite extensive biochemical characterization of NF-κB signaling during the past twenty years, the requirement for NF-κB in tumor development in vivo, particularly in solid tumors, is not completely understood. Here we show that the NF-κB pathway is required for the development of tumors in a mouse model of lung adenocarcinoma. Concomitant loss of p53 and expression of oncogenic K-ras G12D resulted in NF-κB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumor cell lines expressing K-ras G12D and lacking p53, p53 restoration led to NF-κB inhibition. Additionally, inhibition of NF-κB signaling induced apoptosis in p53 null lung cancer cell lines. Inhibition of the pathway in lung tumors in vivo, from the time of tumor initiation or following tumor progression, resulted in significantly reduced tumor development. Together, these results suggest a critical function for NF-κB signaling in lung tumor development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-κB inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in K-ras and p53. Keywords NF-κB; lung adenocarcinoma; mouse modelMore than one million people die from lung cancer each year in the world, making it the leading cause of cancer mortality of both women and men. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases, with adenocarcinoma being the major subtype. NSCLC development is associated with frequent mutations in a few well-defined oncogenes and tumor suppressor genes. Oncogenic K-ras mutations occur in approximately 20-30% of

Activating K-RAS mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream signaling pathways have been shown to be deregulated by oncogenic K-ras. However, to date there are still no effective targeted therapies for this genetically defined subset of patients. Here we report the results of a small molecule, synthetic lethal screen using mouse embryonic fibroblasts derived from a mouse model harboring a conditional oncogenic K-ras G12D allele. Among the >50,000 compounds screened, we identified a class of drugs with selective activity against oncogenic K-ras–expressing cells. The most potent member of this class, lanperisone, acts by inducing nonapoptotic cell death in a cell cycle- and translation-independent manner. The mechanism of cell killing involves the induction of reactive oxygen species that are inefficiently scavenged in K-ras mutant cells, leading to oxidative stress and cell death. In mice, treatment with lanperisone suppresses the growth of K-ras–driven tumors without overt toxicity. Our findings establish the specific antitumor activity of lanperisone and reveal oxidative stress pathways as potential targets in Ras-mediated malignancies.

ImportanceChronic pelvic pain (CPP) is a challenging condition that affects an estimated 26% of the world’s female population. Chronic pelvic pain accounts for 40% of laparoscopies and 12% of hysterectomies in the US annually even though the origin of CPP is not gynecologic in 80% of patients. Both patients and clinicians are often frustrated by a perceived lack of treatments. This review summarizes the evaluation and management of CPP using recommendations from consensus guidelines to facilitate clinical evaluation, treatment, improved care, and more positive patient-clinician interactions.ObservationsChronic pelvic pain conditions often overlap with nonpelvic pain disorders (eg, fibromyalgia, migraines) and nonpain comorbidities (eg, sleep, mood, cognitive impairment) to contribute to pain severity and disability. Musculoskeletal pain and dysfunction are found in 50% to 90% of patients with CPP. Traumatic experiences and distress have important roles in pain modulation. Complete assessment of the biopsychosocial factors that contribute to CPP requires obtaining a thorough history, educating the patient about pain mechanisms, and extending visit times. Training in trauma-informed care and pelvic musculoskeletal examination are essential to reduce patient anxiety associated with the examination and to avoid missing the origin of myofascial pain. Recommended treatments are usually multimodal and require an interdisciplinary team of clinicians. A single-organ pathological examination should be avoided. Patient involvement, shared decision-making, functional goal setting, and a discussion of expectations for long-term care are important parts of the evaluation process.Conclusions and RelevanceChronic pelvic pain is like other chronic pain syndromes in that biopsychosocial factors interact to contribute and influence pain. To manage this type of pain, clinicians must consider centrally mediated pain factors as well as pelvic and nonpelvic visceral and somatic structures that can generate or contribute to pain.