Oncotarget

BUFFALO, NY – July 9, 2025 – A new #review was #published in Volume 16 of Oncotarget on June 25, 2025, titled “Challenges and resistance mechanisms to EGFR targeted therapies in head and neck cancers and breast cancer: Insights into RTK dependent and independent mechanisms.” Researchers from the University of Cincinnati and Cincinnati Veterans Affairs Medical Center reviewed current research on why Epidermal Growth Factor Receptor (EGFR)-targeted therapies often fail in breast and head and neck cancers. The article by Shreya Shyamsunder, Zhixin Lu, Vinita Takiar, and Susan E. Waltz explores how cancer cells evade these treatments by activating alternative survival pathways. This review offers an in-depth look at the molecular barriers to EGFR inhibition and provides insights that could inform the development of more effective and durable treatments. EGFR is a critical protein that regulates cell growth and survival, and it is frequently overexpressed in breast and head and neck cancers. Although therapies targeting EGFR showed early promise, resistance has become a significant challenge. In breast cancer, resistance mechanisms include the movement of EGFR from the cell surface into the nucleus, where it promotes DNA repair, as well as ligand-dependent activation that helps tumor growth despite therapy. In head and neck cancers, resistance often arises from inflammatory signaling through the TLR4-MyD88 pathway and the loss of tumor suppressor genes like PTEN, which allow cancer cells to bypass EGFR inhibition. The review also describes how tumor cells in both cancers commonly activate other receptor tyrosine kinases (RTKs), such as MET, AXL, and RON, to continue growing even when EGFR is blocked. By analyzing these resistance mechanisms, the authors highlight combination therapies from current research that target EGFR and other key molecular pathways. Strategies such as dual inhibition of EGFR and MET or blocking inflammation-driven survival signals may enhance treatment outcomes. Several clinical trials are evaluating these approaches in patients. For example, in breast cancer, combinations of EGFR inhibitors with chemotherapy and immune checkpoint inhibitors are being tested to improve responses, particularly in triple-negative breast cancer. In head and neck cancers, trials are investigating EGFR-blocking antibodies like cetuximab combined with immunotherapies such as pembrolizumab and nivolumab. These efforts aim to overcome resistance and provide more effective treatment options for patients with EGFR-driven tumors. The review also emphasizes the necessity of identifying biomarkers to predict which patients are most likely to benefit from EGFR-based therapies. “A recent phase 1 study has shown that patients with recurrent or metastatic head and neck cancer who received BCA101, a bifunctional dual targeting drug that targets EGFR and TGF-β in combination with pembrolizumab, were able to achieve an overall response rate of 65%.” This work brings together current knowledge about EGFR resistance and illustrates the difficulties involved in treating breast and head and neck cancers. By mapping the many ways tumors overcome EGFR inhibition, the review highlights opportunities for more tailored and effective treatments in the future. DOI - https://doi.org/10.18632/oncotarget.28747 Correspondence to - Susan E. Waltz - susan.waltz@uc.edu, and Vinita Takiar - takiarva@ucmail.uc.edu Video short - https://www.youtube.com/watch?v=RD2W-F3_aX4 About Oncotarget: Website - https://www.oncotarget.com Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY - July 7, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on June 17, 2025, titled “Genetic characteristics of blastic plasmacytoid dendritic cell neoplasm: A single institution experience.” In this study, a research team led by first author Fei Fei and corresponding author Michelle Afkhami from the City of Hope Comprehensive Cancer Center investigated a rare and aggressive type of blood cancer called blastic plasmacytoid dendritic cell neoplasm (BPDCN). Their research uncovered frequent mutations in key genes and identified CCDC50 as a potential biomarker for diagnosis and disease monitoring. These findings could help improve how this cancer is detected and treated in the future. BPDCN most often affects older adults and is known for its rapid progression and poor survival rates. The researchers performed genetic sequencing on 21 patients to better understand the disease. They found that two genes, TET2 and ASXL1, were frequently mutated in these patients and were linked to worse survival, especially in those over 65 years old. “Our study revealed that TET2 (57%) and ASXL1 (33%) were the most frequently mutated genes, followed by NRAS (29%), SRSF2 (14%), ZRSR2 (14%), and KMT2D (14%).” The study also discovered that a gene called CCDC50 was expressed at much higher levels in BPDCN samples compared to other blood cancers, such as acute myeloid leukemia and chronic monomyelocytic leukemia. This suggests that CCDC50 may help clinicians distinguish BPDCN from other similar diseases. Importantly, CCDC50 levels dropped significantly in patients whose disease went into remission, highlighting its potential as a tool for tracking disease activity over time. Researchers further observed that patients who received stem cell transplants lived longer than those who did not, reinforcing the importance of this treatment approach. However, BPDCN remains a challenging disease with an overall poor outlook, making these findings an important step toward better care. This research provides new insights into the genetic changes behind BPDCN and points to CCDC50 as a promising marker to improve diagnosis and monitor treatment success. Larger studies will be needed to confirm these results and bring these discoveries closer to use in routine medical practice. DOI - https://doi.org/10.18632/oncotarget.28742 Correspondence to - Michelle Afkhami - mafkhami@coh.org Video short - https://www.youtube.com/watch?v=wUjr3uU3onI Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28742 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Next-generation sequencing (NGS), CCDC50 To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Liver cancer, especially hepatocellular carcinoma (HCC), remains a major health concern worldwide. In Latin America, the situation becomes more difficult due to limited access to advanced treatments and the high prevalence of underlying liver diseases. A recent research paper, published in Volume 16 of Oncotarget by researchers from Argentina, Brazil, Chile, and Colombia, offers valuable insights into how patients in the region respond to a widely used immunotherapy regimen. This real-world study explores both the effectiveness of treatment and the risks of immune-related side effects. Understanding Hepatocellular Carcinoma: Why It is So Difficult to Treat Hepatocellular carcinoma is often diagnosed at an advanced stage and frequently occurs in people with pre-existing liver conditions such as cirrhosis. Standard treatments like surgery or local therapies are not always possible in these cases. In recent years, the combination of two drugs—atezolizumab and bevacizumab—has shown promise in extending survival. However, most of the evidence comes from controlled clinical trials that may not represent the realities faced by healthcare providers and patients in Latin America. The Study: Immunotherapy for Hepatocellular Carcinoma in Latin America In a multicenter study titled “Immune-mediated adverse events following atezolizumab and bevacizumab in a multinational Latin American cohort of unresectable hepatocellular carcinoma,” led by Leonardo Gomes da Fonseca from Hospital das Clínicas, Universidade de São Paulo, Brazil, and Federico Piñero from Hospital Universitario Austral, Argentina, researchers aimed to fill that gap. The study included 99 patients with advanced HCC from Argentina, Brazil, Chile, and Colombia. All patients received the combination of atezolizumab and bevacizumab. The main objectives were to assess how frequently immune-related side effects, known as immune-related adverse events (irAEs), occurred and whether these events affected overall survival. Full blog - https://www.oncotarget.org/2025/07/02/immunotherapy-safety-for-hepatocellular-carcinoma-in-latin-america-insights-from-a-real-world-study/ Paper DOI - https://doi.org/10.18632/oncotarget.28721 Correspondence to - Federico Piñero - fpinerof@cas.austral.edu.ar Video short - https://www.youtube.com/watch?v=gk3oQwzIC-E Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28721 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, liver cancer, immunotherapy, adverse events, immunology, real-world To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY – July 1, 2025 – A new #review was #published in Volume 16 of Oncotarget on June 17, 2025, titled “Optimizing enfortumab vedotin plus pembrolizumab therapy.” First authors Elias Antoine Karam of the Gustave Roussy and Saint-Joseph University of Beirut and Yaghi César Céline from the Saint-Joseph University of Beirut, along with their colleagues, reviewed recent developments about treating advanced urothelial carcinoma (aUC), an aggressive form of bladder cancer. Their review highlights how combining enfortumab vedotin and pembrolizumab as a first-line treatment offers a major improvement for patients with limited options and poor prognoses. Advanced urothelial cancer has traditionally been treated with platinum-based chemotherapy, which often causes serious side effects and offers limited long-term benefit. Many patients are even ineligible for it due to underlying health conditions. The new combination presents a more effective and better-tolerated alternative, as shown in recent clinical trials reviewed by the authors. Enfortumab vedotin targets Nectin-4, a protein present in most urothelial cancer cells, delivering a cancer-killing agent directly into tumors. Pembrolizumab helps the immune system detect and destroy cancer cells. Together, they have shown strong results in extending survival with fewer serious side effects than chemotherapy. These findings led to FDA approval in 2023 for use in a broad range of patients, including those unable to tolerate traditional treatments. “In the phase II KEYNOTE-052 study, pembrolizumab demonstrated significant efficacy as initial therapy in patients with aUC who were ineligible for a cisplatin-based regimen.” The review also compares this new approach with other evolving strategies, such as therapies using nivolumab and chemotherapy combinations. Among current first-line options, enfortumab vedotin and pembrolizumab have produced the most promising outcomes. However, the best course of action following disease progression remains unclear. Other important challenges raised in the review include the high cost of the new therapies, limited patient access to them, and the absence of reliable biomarkers to predict individual response. The authors call for further studies to refine treatment strategies and explore blood-based tools that could guide therapy decisions and minimize side effects. This review offers a clear summary of how recent clinical advances are reshaping the treatment of aUC. It reflects a shift away from traditional chemotherapy toward immunotherapy and targeted, personalized treatments that aim to extend survival and improve quality of life. DOI - https://doi.org/10.18632/oncotarget.28741 Correspondence to - Elias Antoine Karam - eliaskaram18@gmail.com Video short - https://www.youtube.com/watch?v=VrTXaF2qW2k Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28741 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, advanced urothelial carcinoma (aUC), enfortumab vedotin, pembrolizumab, treatment strategies, bladder cancer To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY – June 27, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on June 17, 2025, titled “Molecular landscape of HER2-mutated non-small cell lung cancer in Northeastern Brazil: Clinical, histopathological, and genomic insights.” In this study, researchers led by first authors Cleto Dantas Nogueira from the Federal University of Ceará and Argos Pathology Laboratory and Samuel Frota from Argos Pathology Laboratory, along with corresponding author Fabio Tavora from the previously mentioned institutions and Messejana Heart and Lung Hospital, investigated how HER2 gene mutations appear in cases of non-small cell lung cancer (NSCLC) in Northeastern Brazil. The team found that HER2 mutations showed significant genetic diversity and were often associated with other cancer-related genetic changes. These findings revealed diagnostic and treatment challenges in a population that is rarely studied, emphasizing the need for expanded access to molecular testing and targeted therapies. HER2 mutations are a known factor in several cancers, including breast and gastric cancers. In lung cancer—particularly NSCLC—these mutations are less common but remain clinically significant. Most existing research on HER2-mutated lung cancer focuses on high-income countries, leaving important gaps in knowledge about underrepresented regions such as Latin America. This study helps fill that gap by analyzing 13 patients with HER2-mutated NSCLC using clinical, pathological, and genomic data. The patients ranged in age from 34 to 82 years, and more than half were women. About half had never smoked. Their tumors often displayed complex genetic profiles, including additional mutations in genes such as TP53, KRAS, and STK11. The most common HER2 mutation identified was an insertion in exon 20, a known hotspot for activating mutations. “Trastuzumab deruxtecan (T-DXd) is the first HER2-targeted agent to show clinical efficacy in HER2-mutant non-small cell lung cancer (HER2m NSCLC).” Treatment strategies among the patients varied. Only one individual received HER2-targeted therapy. Most were treated with surgery, chemotherapy, immunotherapy, or a combination of these approaches. Outcomes also differed, with some patients surviving for years and others dying within months of diagnosis. These findings reinforce the need for early diagnosis and improved access to advanced treatments, particularly in low-resource settings. The study emphasizes the value of comprehensive molecular profiling in NSCLC. Because HER2 mutations often occur alongside other genetic alterations, full genomic analysis is crucial for guiding treatment decisions. Yet, such testing is not always available. The researchers propose a tiered diagnostic approach, beginning with basic screening and expanding to more advanced tests when necessary, to enhance patient care. This study provides valuable insights into the molecular characteristics of HER2-mutated NSCLC in a Brazilian population, highlighting the complexity and clinical relevance of these alterations. Larger studies are needed to clarify the prevalence and prognostic significance of HER2 mutations, as well as their impact on treatment response and survival. This knowledge is essential for advancing effective HER2-targeted therapies. The findings also support broader implementation of international clinical guidelines in Latin America and highlight the critical need to include underrepresented populations in cancer research. DOI - https://doi.org/10.18632/oncotarget.28737 Correspondence to - Fabio Tavora - stellacpak@outlook.com Video short - https://www.youtube.com/watch?v=hr5R9iDBFFI To learn more about Oncotarget, please visit https://www.oncotarget.com. MEDIA@IMPACTJOURNALS.COM