NRF2 Signaling Pathway in Chemo/Radio/Immuno-Therapy Resistance of Lung Cancer: Looking Beyond the Tip of the Iceberg.

Lung cancer is one of the most common causes of cancer death in men and women worldwide. Various combinations of surgery, chemotherapy, radiation therapy and immunotherapy are currently used to treat lung cancer. However, the prognosis remains relatively poor due to the higher frequency of tumor mutational burden (TMB). Nuclear factor E2-related factor 2 (NFE2L2/NRF2) is often considered a primary regulator of the expression of antioxidant enzymes and detoxification proteins and is involved in cytoprotection. On the contrary, NRF2 is even known to induce metastasis and support tumor progression. Kelch-like ECH-associated protein 1 (KEAP1) plays an important role in negatively regulating NRF2 activity via CUL3-mediated ubiquitinylation and successive proteasomal degradation. Extensive research has shown that the genetic alterations of KEAP1/NFE2L2/CUL3 genes lead to increased expression of NRF2 and its target genes in lung cancer. Thus, these studies provide ample evidence for the dual role of NRF2 in lung cancer. In this review, we discussed the mechanistic insights into the role of NRF2 signaling in therapy resistance by focusing on cell lines, mouse models, and translational studies in lung cancer. Finally, we highlighted the potential therapeutic strategies targeting NRF2 inhibition, followed by the discussion of biomarkers related to NRF2 activity in lung cancer. Overall, our article exclusively discusses in detail the NRF2 signaling pathway in resistance to therapy, especially immunotherapy, and its therapeutic avenue in the treatment of lung cancer.

Ogilvie Syndrome in a Refractory Germ Cell Tumor Treated with Vinblastine, Ifosfamide and Cisplatin Regimen.

Ogilvie syndrome or intestinal pseudo-obstruction is a clinical syndrome characterized by autonomic imbalance affecting peristalsis of colon leading to obstructive signs and symptoms. The etiologies commonly implicated are drugs affecting the cholinergic system, narcotics, electrolyte imbalance, severe sepsis, cancer, major surgery, and renal and cardiac failure. Ogilvie syndrome secondary to chemotherapy is a very rare phenomenon with very few reports in the literature. Cisplatin-induced neuropathy has been reported to occur when the cumulative dose exceeds 360 mg/m2. It manifests predominantly as peripheral sensory neuropathy with autonomic neuropathy occurring very rarely in a subset of patients. All the reported cases to date who presented with autonomic dysfunction secondary to cisplatin also had peripheral sensory neuropathy. Herein, we report a case of metastatic nonseminomatous germ cell tumor treated with cisplatin based regimen, who presented with severe intestinal pseudo-obstruction when the cumulative dose exceeded 400 mg/m2 without any other manifestation of neuropathy. To our knowledge this is the first such case reported in the literature.

Frequency and Prognosis of Epidermal Growth Factor Receptor Variant III Mutations in Glioblastoma Multiforme among Indian Patients: A Single-Institution Study.

Background Glioblastoma multiforme (GBM) is a disease with poor outcome. Alterations or mutations in epidermal growth factor receptors (EGFRs) are found in GBM and may be targeted to improve outcomes. Aims We analyzed the frequency of EGFR variant III (vIII) mutations in patients with GBM and their outcomes after standard treatment. Materials and Methods This is a retrospective study conducted in a single tertiary cancer center in south India. Forty patients with GBM who had their entire treatment done at this center were identified, and their primary tumor tissue blocks were retrieved. Genomic DNA was extracted, and molecular analysis was performed and analyzed. The results of mutational analysis were correlated with treatment outcome of the patients. Statistical Analysis Survival outcome was analyzed using the Kaplan-Meier method. The log-rank test was used to assess the association between the groups and various parameters. Results Our study showed a similar incidence of EGFR vIII alterations as published in world literature, but we did not find any difference in overall survival (OS) and progression-free survival (PFS) in patients with EGFR vIII mutation compared with nonmutant cohort. Conclusions Contrary to the existing literature which indicated EGFR vIII alterations to be a negative prognostic indicator, our study did not find it to be an independent predictor of prognosis among Indian GBM patients treated with present standard of care.