Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis.

Efforts to improve the clinical outcome of highly aggressive triple-negative breast cancer (TNBC) have been hindered by the lack of effective targeted therapies. Thus, it is important to identify the specific gene targets/pathways driving the invasive phenotype to develop more effective therapeutics. Here we show that ubiquitin-associated and SH3 domain-containing B (UBASH3B), a protein tyrosine phosphatase, is overexpressed in TNBC, where it supports malignant growth, invasion, and metastasis largely through modulating epidermal growth factor receptor (EGFR). We also show that UBASH3B is a functional target of anti-invasive microRNA200a (miR200a) that is down-regulated in TNBC. Importantly, the oncogenic potential of UBASH3B is dependent on its tyrosine phosphatase activity, which targets CBL ubiquitin ligase for dephosphorylation and inactivation, leading to EGFR up-regulation. Thus, UBASH3B may function as a crucial node in bridging multiple invasion-promoting pathways, thereby providing a potential therapeutic target for TNBC.

Redefining the Role of Medical Affairs Professionals as Innovators and Leaders in Industry-Led Medical Education.

Medical affairs professionals are pivotal players at the intersection of medical innovation and practice in the pharmaceutical industry. They are uniquely positioned to translate complex medical knowledge into actionable insights for internal and external stakeholders. Industry-led continuing medical education (CME) programs, guided by these professionals, hold the potential to markedly improve clinicians' application of evidence-based medicine (EBM) in clinical settings, thereby elevating patient care outcomes. However, current CME techniques often overlook the integration of diverse disciplines such as educational theories, cognitive psychology, information mastery, and implementation science, which are important for effective real-time decision-making in patient care. This gap in integrating implementation science is vital, as it is key in ensuring that medical innovations are not just developed but also effectively implemented and efficiently utilized in clinical settings. In this opinion article, we aim to highlight the crucial yet often underrecognized role of medical affairs professionals in shaping robust and practical CME programs within the industry. We explore emerging trends and approaches in medical education and CME based on the principles of adult education. Additionally, we explore how medical affairs professionals can effectively drive the adoption of EBM in clinical practice. This exploration aims to provide insights into enhancing CME programs, with medical affairs professionals at the forefront of innovation and leadership in bridging gaps in clinical practice.

Asian Subgroup Analysis of the Randomized Phase 3 CROWN Study of First-Line Lorlatinib Versus Crizotinib in Advanced ALK-Positive NSCLC.

Introduction: Lorlatinib is a potent, third-generation inhibitor of ALK. In the planned interim analysis of the ongoing, phase 3, randomized, global CROWN trial (NCT03052608), lorlatinib resulted in significantly longer progression-free survival than crizotinib in patients with previously untreated, advanced, ALK-positive NSCLC. Here, we present a subgroup analysis of Asian patients in the CROWN study. Methods: Patients received lorlatinib 100 mg once daily or crizotinib 250 mg twice daily. The primary end point was progression-free survival assessed by blinded independent central review. Objective response rate (ORR), intracranial ORR, safety, and select biomarkers were secondary end points. Results: At data cutoff (September 20, 2021), 120 patients were included in the Asian intention-to-treat subgroup (lorlatinib n = 59; crizotinib n = 61). At 36 months, 61% (95% confidence interval [CI]: 47-72) and 25% (95% CI: 12-41) of patients in the lorlatinib and crizotinib groups, respectively, were alive without disease progression (hazard ratio for disease progression by blinded independent central review or death: 0.40; 95% CI: 0.23-0.71). ORR was 78% (95% CI: 65-88) versus 57% (95% CI: 44-70) for patients treated with lorlatinib and crizotinib, respectively. In patients with measurable, nonmeasurable, or both measurable and nonmeasurable brain metastases at baseline, intracranial ORR was 73% (95% CI: 39-94) versus 20% (95% CI: 4-48) for patients treated with lorlatinib and crizotinib, respectively. The definition of nonmeasurable brain metastases is: a brain lesion less than 10 mm in MRI scan is defined as nonmeasurable brain metastasi based on RECIST criteria (Clinical trial evaluation criteria). Hypercholesterolemia, hypertriglyceridemia, and edema were the most frequently reported adverse events with lorlatinib. Conclusions: Lorlatinib efficacy and safety in the Asian subgroup of CROWN were consistent with those in the overall population.

Digital Transformation in Medical Affairs Sparked by the Pandemic: Insights and Learnings from COVID-19 Era and Beyond.

A number of developments, including increasing regulatory and compliance scrutiny, increased transparency expectations, an increasingly vocal patient, patient centricity and greater requirements for real-world evidence, have driven the growth and importance of medical affairs as a trusted, science-driven partner over the past decade. The healthcare environment is shifting towards a digital, data-driven and payor-focused model. Likewise, medical affairs as a function within the pharmaceutical industry has become more "patient-centric" with strategic engagements embracing payers and patients apart from clinicians. The pandemic has impacted the healthcare industry as well as the function of medical affairs in numerous ways and has brought new challenges and demands to tackle. There is indeed a silver lining due to intense digital transformation within this crisis. The emerging digital innovation and new technologies in healthcare, medical education and virtual communications are likely to stay and advance further. In this review, we discuss how the digital transformation sparked by the pandemic has impacted the medical affairs function in pharmaceuticals and provide further insights and learnings from the COVID-19 era and beyond. Based on the learning and insights, digital innovation in three key strategic imperatives of medical affairs-HCP engagement, external partnerships and data generation will enable medical affairs to become future-fit as a strategic leadership function.

Safety and efficacy of first-line dacomitinib in Asian patients with EGFR mutation-positive non-small cell lung cancer: Results from a randomized, open-label, phase 3 trial (ARCHER 1050).

OBJECTIVES: To compare efficacy and safety of dacomitinib versus gefitinib as first-line therapy for EGFR mutation-positive advanced NSCLC in Asian patients enrolled in the ongoing ARCHER 1050 trial. MATERIALS AND METHODS: In this ongoing, randomized, open-label, phase 3 trial (NCT01774721), eligible patients with newly diagnosed advanced EGFR mutation-positive NSCLC were randomized (1:1) to receive oral dacomitinib 45 mg/day or oral gefitinib 250 mg/day. Randomization, by a central computer system, was stratified by race and EGFR mutation type (exon 19 deletion mutation/exon 21 L858R substitution mutation). The primary endpoint was PFS by blinded independent review. RESULTS: Of 346 Asian patients, 170 were randomized to dacomitinib and 176 to gefitinib. The hazard ratio (HR) for PFS with dacomitinib versus gefitinib was 0.509 (95 % confidence interval [CI]: 0.391-0.662; 1-sided p < 0.0001; median 16.5 months [95 % CI: 12.9-18.4] vs. 9.3 months [95 % CI: 9.2-11.0]). HR for OS with dacomitinib versus gefitinib was 0.759 (95 % CI: 0.578-0.996; median 37.7 months [95 % CI: 30.2-44.7] vs. 29.1 months [95 % CI: 25.6-36.0]). The OS benefit was still maintained in those patients who had a stepwise dose reduction of dacomitinib (to 30 and 15 mg/day). The most common adverse events (AEs) were diarrhea (154 [90.6 %] patients), paronychia (110 [64.7 %]), dermatitis acneiform (96 [56.5 %]), and stomatitis (87 [51.2 %]) with dacomitinib, and diarrhea (100 [56.8 %]), alanine aminotransferase increased (81 [46.0 %]), and aspartate aminotransferase increased (75 [42.6 %]) with gefitinib. Treatment-related serious AEs were reported in 16 (9.4 %) and 8 (4.5 %) patients treated with dacomitinib and gefitinib, respectively. CONCLUSION: First-line dacomitinib was associated with significant prolongation of PFS and improved OS compared with gefitinib in Asian patients with EGFR mutation-positive advanced NSCLC. The AE profiles of dacomitinib and gefitinib in Asian patients were consistent with the overall ARCHER 1050 population.

Correction: Simultaneous Induction of Non-Canonical Autophagy and Apoptosis in Cancer Cells by ROS-Dependent ERK and JNK Activation.

[This corrects the article DOI: 10.1371/journal.pone.0009996.].

Simultaneous induction of non-canonical autophagy and apoptosis in cancer cells by ROS-dependent ERK and JNK activation.

BACKGROUND: Chemotherapy-induced reduction in tumor load is a function of apoptotic cell death, orchestrated by intracellular caspases. However, the effectiveness of these therapies is compromised by mutations affecting specific genes, controlling and/or regulating apoptotic signaling. Therefore, it is desirable to identify novel pathways of cell death, which could function in tandem with or in the absence of efficient apoptotic machinery. In this regard, recent evidence supports the existence of a novel cell death pathway termed autophagy, which is activated upon growth factor deprivation or exposure to genotoxic compounds. The functional relevance of this pathway in terms of its ability to serve as a stress response or a truly death effector mechanism is still in question; however, reports indicate that autophagy is a specialized form of cell death under certain conditions. METHODOLOGY/PRINCIPAL FINDINGS: We report here the simultaneous induction of non-canonical autophagy and apoptosis in human cancer cells upon exposure to a small molecule compound that triggers intracellular hydrogen peroxide (H(2)O(2)) production. Whereas, silencing of beclin1 neither inhibited the hallmarks of autophagy nor the induction of cell death, Atg 7 or Ulk1 knockdown significantly abrogated drug-induced H(2)O(2)-mediated autophagy. Furthermore, we provide evidence that activated extracellular regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) are upstream effectors controlling both autophagy and apoptosis in response to elevated intracellular H(2)O(2). Interestingly, inhibition of JNK activity reversed the increase in Atg7 expression in this system, thus indicating that JNK may regulate autophagy by activating Atg7. Of note, the small molecule compound triggered autophagy and apoptosis in primary cells derived from patients with lymphoma, but not in non-transformed cells. CONCLUSIONS/SIGNIFICANCE: Considering that loss of tumor suppressor beclin 1 is associated with neoplasia, the ability of this small molecule compound to engage both autophagic and apoptotic machineries via ROS production and subsequent activation of ERK and JNK could have potential translational implications.