Pancreatic ductal adenocarcinoma (PDAC) is associated with a 5-year overall survival rate of just 13%, and development of chemotherapy resistance is nearly universal. PDAC cells overexpress wild-type isocitrate dehydrogenase 1 (IDH1) that can enable them to overcome metabolic stress, suggesting it could represent a therapeutic target in PDAC. Here, we found that anti-IDH1 therapy enhanced the efficacy of conventional chemotherapeutics. Chemotherapy treatment induced reactive oxygen species (ROS) and increased tricarboxylic acid cycle activity in PDAC cells, along with the induction of wild-type IDH1 expression as a key resistance factor. IDH1 facilitated PDAC survival following chemotherapy treatment by supporting mitochondrial function and antioxidant defense to neutralize ROS through the generation of α-ketoglutarate and NADPH, respectively. Pharmacologic inhibition of wild-type IDH1 with ivosidenib synergized with conventional chemotherapeutics in vitro and potentiated the efficacy of subtherapeutic doses of these drugs in vivo in murine PDAC models. This promising treatment approach is translatable through available and safe oral inhibitors and provides the basis of an open and accruing clinical trial testing this combination (NCT05209074). Significance: Targeting IDH1 improves sensitivity to chemotherapy by suppressing mitochondrial function and inducing oxidative stress, supporting the potential of the combination as an effective strategy for treating pancreatic cancer.

HER3, formally referred to as ERB-B2 receptor tyrosine kinase 3, is a member of the ErbB receptor tyrosine kinases (also known as EGFR) family. HER3 plays a significant pro-cancer role in various types of cancer due to its overexpression and abnormal activation, which initiates downstream signaling pathways crucial in cancer cell survival and progression. As a result, numerous monoclonal antibodies have been developed to block HER3 activation and subsequent signaling pathways. While pre-clinical investigations have effectively showcased significant anti-cancer effects of HER3-targeted therapies, these therapies have had little impact on cancer patient outcomes in the clinic, except for patients with rare NRG1 fusion mutations. This review offers a comprehensive description of the oncogenic functions of HER3, encompassing its structure and mediating signaling pathways. More importantly, it provides an in-depth exploration of past and ongoing clinical trials investigating HER3-targeted therapies for distinct types of cancer and discusses the tumor microenvironment and other critical determinants that may contribute to the observed suboptimal outcomes in most clinical studies using HER3-targeted therapies. Lastly, we suggest alternative approaches and the exploration of novel strategies to potentially improve the efficacy of targeting the pivotal oncogenic HER3 signaling pathway in future translational investigations.

Objective: To quantify the extent of the disruption and recovery of lung cancer detection during the first two years of the pandemic, focusing on disparities across demographic and community factors. Methods: This retrospective cohort study used the SEER database to identify lung cancer cases from 2001 to 2021. Expected incidence rates for 2020 and 2021 were projected based on pre-pandemic trends (2000–2019) using the NCI’s Joinpoint Regression program. Percent differences between expected and observed incidence rates were calculated. Multivariate and propensity score analyses were conducted to quantify changes in the odds of being diagnosed with metastatic disease during the pandemic. Results: Lung cancer incidence fell by 10% in 2020 compared to pre-pandemic projections, with rural populations, non-Hispanic Black and Asian patients, and females disproportionately affected. By 2021, detection rates partially recovered but remained 5% below expected levels. Localized disease detection improved significantly, while rural communities not adjacent to metropolitan areas faced further declines. Adjusted analyses showed that patients with small-cell lung cancer (SCLC) and those of Hispanic, non-Hispanic Black, or Asian/Pacific Islander ethnicity had persistently higher rates of distant disease presentation through 2021. Conclusions: The pandemic significantly reduced lung cancer detection, with only partial recovery by 2021. Persistent gaps, particularly in rural and minoritized populations, highlight the need for targeted interventions to reengage these communities.