Pasi A. Jänne

RAF isoform selectivity of MEK inhibitors and rational design of a covalent ARAF-MEK inhibitor

Aberrant activation of the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal–regulated kinase pathway is a frequent cause of cancer. Allosteric MEK inhibitors block this pathway by binding RAF-MEK complexes to prevent activation of MEK by RAF. However, how MEK inhibitor potency varies across the three RAF isoforms remains poorly understood. We profiled seven allosteric MEK inhibitors and observed a notable hierarchy of sensitivity: All most potently inhibited CRAF-driven MEK activation while relatively sparing ARAF-driven activation. We identified point mutations in ARAF and CRAF proximate to the MEK inhibitor binding site that markedly altered inhibitor sensitivity. Using a rational design approach, we developed a more potent inhibitor of ARAF-driven MEK signaling, TWG-07-148. Our cryo–electron microscopy structure shows how this acrylamide-containing analog of MEK inhibitor trametinib covalently targets Cys 514 , a residue unique to ARAF. Our studies highlight the importance of the activating RAF isoform as a determinant of MEK inhibitor sensitivity and provide proof of concept for the development of MEK inhibitors that more effectively block ARAF-driven MEK signaling via covalent targeting of Cys 514 .

Centromere-Targeting Chimeras for Combating Cancer Drug Resistance

Centromere protein B (CENPB), the only sequence-specific DNA-binding protein at centromeres, maintains chromosomal stability and accurate mitotic segregation. Its overexpression in aggressive cancers is associated with aneuploidy and poor prognosis, yet CENPB remains therapeutically underexplored because direct inhibitors are unavailable. Here, we develop CENPB OligoTAC, a DNA-based PROTAC comprising a CENPB-binding oligodeoxynucleotide linked to an E3 ligase ligand. CENPB OligoTAC induces ubiquitination and proteasomal degradation of CENPB, disrupting centromere integrity, causing chromosome mis-segregation, and activating apoptosis. It shows potent activity in preclinical non-small cell lung cancer models resistant to first-, second-, and third-generation tyrosine kinase inhibitors, while exhibiting minimal cytotoxicity toward normal cells and good serum stability. In vivo, CENPB OligoTAC demonstrates favorable pharmacokinetics, good tolerability, and no significant hematological changes. By exploiting cancer cells’ dependence on centromeric stability, this platform offers a novel strategy for selectively targeting aneuploid malignancies.

A study to learn how well HER3-DXd (patritumab deruxtecan) works and how safe it is in people with previously treated non-small-cell lung cancer that has a mutation in the EGFR gene: a plain language summary of the HERTHENA-Lung01 study

Plain Language SummaryWhat is this summary about?This is a summary of the publication about the HERTHENA-Lung01 study, which was published in the Journal of Clinical Oncology in September 2023. The study included 277 adults with non-small-cell lung cancer (NSCLC) that had a mutation in a gene called EGFR. The researchers wanted to know whether a study drug called HER3-DXd (patritumab deruxtecan) could improve participants’ cancer after it had grown after previous treatment with certain other cancer drugs.What are the key takeaways?About 3 out of every 10 participants responded to treatment with HER3-DXd at some point during the study, which means their cancer shrank significantly or disappeared. Among the participants who benefited, about half had their cancer continue to respond to HER3-DXd for longer than 6.4 months before growing or spreading.After starting treatment with HER3-DXd, about half of the participants lived for longer than about 5.5 months before their cancer grew, spread, or caused death, and for longer than about 11.9 months overall.For participants with brain metastases, 1 out of every 3 participants had their brain metastases respond to treatment with HER3-DXd. About half of these participants had their brain metastases continue to respond to HER3-DXd for longer than about 8 months.About 6 out of every 10 participants had a severe new medical issue during the study, either related or unrelated to HER3-DXd.Almost all participants had a new medical issue during the study that was possibly related to HER3-DXd. About 1 out of every 20 participants had interstitial lung disease (ILD) or pneumonitis that was possibly related to HER3-DXd.What were the main conclusions reported by the researchers?HER3-DXd has been shown to be effective for people who have NSCLC with certain EGFR mutations and whose cancer has progressed after multiple previous treatments. People who receive HER3-DXd should be watched closely for signs of interstitial lung disease (ILD) or pneumonitis. These are the results from one study, and other studies might provide different results. This study did not directly compare HER3-DXd with any other cancer treatments. Always talk to your doctor before making any changes to your medication. Further studies with HER3-DXd are planned and multiple studies are ongoing.Clinical trial number: NCT04619004

Overcoming EGFR Resistance by Monovalent and Bident Inhibitors Targeting Cys775

Covalent targeting of EGFR cysteine 797 by osimertinib is one of the most successful breakthroughs in targeted therapy, fundamentally transforming the treatment landscape for non-small-cell lung cancer (NSCLC) patients. However, resistance driven by the mutation of C797 remains a major clinical challenge. Developing novel covalent strategies beyond C797 targeting presents a compelling opportunity for next-generation EGFR inhibitors. We first demonstrated that cysteine 775, located deep within the ATP-binding pocket, is accessible by a rationally designed covalent molecule ZNL-3, which as the first-in-class covalent cysteine 775 inhibitor exhibited strong efficacy in osimertinib-resistant mouse models. To further enhance resilience to resistance-causing mutations, we developed a dual-warhead, bident compound YNW-1 which covalently targets both cysteines 775 and 797 simultaneously. YNW-1 is the first intramolecular lock to exhibit balanced reactive efficiency on both cysteines, rendering single-site mutations ineffective at conferring resistance. This study establishes the therapeutic potential of an EGFR covalent inhibitor through unprecedented targeting of cysteine 775. It also provides the first evidence that dual-cysteine engagement offers superior efficacy to conventional covalent inhibitors by delaying the emergence of resistance. Further optimization for clinical translation is currently ongoing in our laboratory.

Germline EGFR T790M mutation and lung cancer risk

Most lung cancers are tobacco related, with genetic factors influencing smoking behavior identified through genome-wide association studies. However, inherited risk in familial and non-smoking-related lung cancers, including risk in carriers of EGFR T790M, remains poorly understood. Here, in more than 3.3 million individuals, the EGFR T790M germline variant is significantly associated with lung cancer risk, with no increased risk for 17 other cancers and no interaction with polygenic risk. This risk exceeds that conferred by smoking and is several-fold higher in never-smokers. Global geographic and ancestry analyses show higher T790M prevalence in the US than in British- and Irish-descendant populations, reflecting a Southern Appalachian founder event about 200 to 225 years ago, increasing regional prevalence and affecting those of British, Irish, and African descent. Recognition of high-risk carriers may inform targeted genetic testing and screening strategies.

Long-term safety of first-line osimertinib plus platinum–pemetrexed in EGFR-mutated advanced NSCLC: FLAURA2

INTRODUCTION: In the phase 3 FLAURA2 trial (NCT04035486), adding platinum-pemetrexed to first-line osimertinib significantly improved survival versus osimertinib monotherapy. We report a long-term longitudinal safety analysis, including incidence and temporal patterns of treatment-emergent adverse events (AEs). METHODS: Patients with EGFR-mutated advanced NSCLC were randomized to either osimertinib plus platinum-pemetrexed (for four cycles, followed by osimertinib plus pemetrexed maintenance), or osimertinib monotherapy. A post-hoc analysis of the combination arm, tailored to individual patients' exposure to each study treatment, was conducted to characterize the safety of three distinct treatment periods: induction (triple-combination therapy; n = 276), pemetrexed-maintenance (osimertinib-plus-pemetrexed; n = 201), and osimertinib-only (n = 206). RESULTS: In the combination arm, median (range) duration of each period was 2.8 (0.1-4.1), 12.4 (0.7-56.1), and 17.8 (0.4-56.8) months, respectively. Onset frequency of any-grade/grade ≥ 3 AEs causally related to treatment was highest during induction (93%/43%), decreasing progressively across the pemetrexed-maintenance (90%/25%) and osimertinib-only (58%/14%) periods. New AEs indicative of hematological, gastrointestinal, and skin/nail toxicity (mostly grade 1/2) were reported most frequently during induction, with reductions in frequency thereafter. Onset frequency of AEs indicative of renal toxicity was higher during pemetrexed maintenance (19%; all grade 1/2) than induction (7%; one grade 3). Rates of AEs leading to osimertinib discontinuation were low across periods (≤8%). CONCLUSIONS: By characterizing safety according to individual treatment exposure, this novel analysis provides insight into the longitudinal safety of the FLAURA2 regimen. With prolonged treatment, grade ≥ 3 AE onset frequency progressively declined over successive treatment periods, while AE profiles remained consistent with the known safety profiles of the individual agents. Median durations of the pemetrexed-maintenance and osimertinib-only periods exceeded 12 and 17 months, respectively. This reinforces the favorable long-term benefit-risk profile of the FLAURA2 regimen. CLINICALTRIALS: gov: NCT04035486.

Presenting features and outcomes to standard systemic therapies in patients with MTAP-deleted advanced non-small cell lung cancer

Retrospective study identifies aggressive features and poor outcomes in advanced MTAP-deleted lung cancer, suggesting improved treatments are needed.

Co-Targeting EZH2 and TEAD Induces Apoptosis in Hippo Pathway-Altered Cancers

This research demonstrates that co-targeting EZH2 and TEAD enhances apoptosis in Hippo pathway-mutated cancers, suggesting a new treatment approach.

Patterns of lung cancer incidence in adults diagnosed under age 50 in the United States, 2000–2021

BACKGROUND: Although the incidence of several cancers diagnosed before age 50 years has increased, contemporary trends in early-onset lung cancer remain poorly defined, particularly across histologic and sociodemographic subgroups. METHODS: A population-based cohort study was conducted via Surveillance, Epidemiology, and End Results 22 Program registries of 81,568 individuals diagnosed with lung cancer at age 20-49 years from 2000 to 2021. Age-adjusted incidence rates and annual percent change (APC) were estimated via National Cancer Institute Joinpoint regression. Overall trends were stratified by histology, sex, race/ethnicity, and state-level smoking prevalence. RESULTS: From 2000 to 2021, early-onset lung cancer incidence declined overall (average APC, -3.81%; 95% CI, -4.01% to -3.64%; p < .0001), which contrasts with rising early-onset colorectal and female breast cancers. Declines among females occurred later but were steeper for lung adenocarcinoma (LUAD; -5.14% vs. -2.82%), whereas males declined faster for non-small cell lung cancer (NSCLC) and overall. Female declines were slower relative to males in Hispanic and non-Hispanic (NH) Black individuals (2.3- and 1.08-fold difference, respectively), whereas NH White females declined 1.3-fold faster than males. Among Asian females, NSCLC incidence did not decline, and LUAD increased through 2017 (+2.45%) and remained stable in Hispanic females. In high-smoking states, male rates declined steadily (-4.32%), whereas female rates were stable until 2010, then dropped sharply, and converged with males by 2021. In low-smoking states, male rates declined 48.75% faster than female rates (-4.76% vs. -3.20%). CONCLUSIONS: Early-onset lung cancer incidence declined overall from 2000 to 2021, except for persistent or rising LUAD among Asian and Hispanic females, which implicates emerging non-tobacco risk factors and highlights the need for targeted prevention.

RAF isoform selectivity of MEK inhibitors and rational design of a covalent ARAF-MEK inhibitor

Biochemical analysis reveals distinct RAF isoform sensitivities to MEK inhibitors in kinase complexes, highlighting covalent targeting to overcome weak ARAF inhibition.

Overcoming EGFR resistance by monovalent and bident inhibitors targeting Cys775

Covalent targeting of EGFR cysteine 797 by osimertinib is one of the most successful breakthroughs in targeted therapy, fundamentally transforming the treatment landscape for non-small cell lung cancer (NSCLC) patients. However, resistance driven by mutation of C797 remains a major clinical challenge. Developing novel covalent strategies beyond C797 targeting presents a compelling opportunity for next-generation EGFR inhibitors. We first demonstrated that cysteine 775, located deep within the ATP-binding pocket, is accessible by a rationally designed covalent molecule ZNL-3, which as the first-in-class covalent cysteine 775 inhibitor exhibited strong efficacy in osimertinib-resistant mouse models. To further enhance resilience to resistance-causing mutations, we developed a dual-warhead, bident compound-YNW-1-which covalently targets both cysteine 775 and 797 simultaneously. YNW-1 is the first intramolecular lock to exhibit balanced reactive efficiency on both cysteines, rendering single-site mutations ineffective to confer resistance. The discovery of ZNL-3 and YNW-1 represents significant advancements in EGFR-targeted drug development, and further optimization toward clinical translation is a worthwhile strategy. SIGNIFICANCE: This study establishes the therapeutic potential of an EGFR covalent inhibitor through unprecedented targeting of cysteine 775 and provides the first demonstration that dual cysteine engagement offers superior efficacy over conventional covalent inhibitors by delaying resistance.

NOV 2025JänneJAMA Network Open

Trastuzumab Deruxtecan for ERBB2 -Mutant Metastatic Non–Small Cell Lung Cancer With or Without Brain Metastases

Importance: Brain metastases reduce overall survival rates of patients with non-small cell lung cancer (NSCLC); patients with epidermal growth factor receptor 2 (ERBB2 [formerly HER2])-mutant NSCLC are more likely to have baseline brain metastases. Trastuzumab deruxtecan (T-DXd) is an approved ERBB2-directed treatment for previously treated unresectable or metastatic ERBB2-mutant NSCLC. Objective: To assess the clinical effectiveness and safety of T-DXd 5.4 mg/kg and 6.4 mg/kg doses in patients with previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases. Design, Setting, and Participants: This post hoc secondary analysis pooled patients from the DESTINY-Lung01 (data cutoff date: December 3, 2021) and DESTINY-Lung02 (data cutoff date: December 23, 2022) clinical trials by T-DXd dose (5.4 mg/kg and 6.4 mg/kg). DESTINY-Lung01 was a multicenter, open-label, 2-cohort, nonrandomized phase 2 study, while DESTINY-Lung02 was a dose-blinded, multicenter, 2-cohort, randomized phase 2 study. Participants had a previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases at baseline. All statistical analyses were performed from April 2023 to October 2024. Intervention: Patients received a T-DXd dose of either 5.4 mg/kg or 6.4 mg/kg intravenously every 3 weeks. Main Outcome and Measure: Systemic and intracranial effectiveness by blinded independent central review using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, sites of progression, and safety. Results: This analysis included 102 patients in the T-DXd 5.4-mg/kg dose group (65 females [64%]; median [range] age, 57.5 [37.0-83.0] years and 59.5 [30.0-79.0] years in patients with and without brain metastases, respectively) and 141 patients in the T-DXd 6.4-mg/kg dose group (94 females [67%]; median [range] age, 62.5 [29.0-88.0] years and 59.0 [27.0-83.0] years in patients with and without brain metastases, respectively). In each group, 31% (32 of 102) and 38% (54 of 141) of patients, respectively, had baseline brain metastases and 53% (17 of 32) and 44% (24 of 54), respectively, received prior brain metastasis treatment. In patients with and without brain metastases, systemic confirmed objective response rates (ORRs) were 47% (15 of 32; 95% CI, 29%-65%) and 50% (35 of 70; 95% CI, 38%-62%), respectively, with the T-DXd 5.4-mg/kg dose, and 50% (27 of 54; 95% CI, 36%-64%) and 59% (51 of 87; 95% CI, 48%-69%) with the T-DXd 6.4-mg/kg dose. Median progression-free survival was 7.1 (95% CI, 5.5-9.7) months in the T-DXd 5.4-mg/kg dose group and 7.1 (95% CI, 4.5-9.6) months in the T-DXd 6.4-mg/kg dose group of patients with baseline brain metastases. Among patients with measurable baseline brain metastases, intracranial confirmed ORRs were 50% (7 of 14; 95% CI, 23%-77%) with the T-DXd 5.4-mg/kg dose and 30% (9 of 30; 95% CI, 15%-49%) with the T-DXd 6.4-mg/kg dose. At both doses, the safety profile of T-DXd was generally manageable, regardless of baseline brain metastases, favoring the T-DXd 5.4 mg/kg dose. Conclusions and Relevance: In this secondary analysis, T-DXd at the approved dose of 5.4 mg/kg showed antitumor activity in patients with previously treated ERBB2-mutant metastatic NSCLC with or without brain metastases. This finding supports T-DXd 5.4 mg/kg use in this population.

Phase I/II Study of AXL-Specific Antibody–Drug Conjugate Enapotamab Vedotin in Patients with Advanced Solid Tumors

Phase 1/2 trial demonstrates modest antitumor activity with manageable safety of enapotamab vedotin in advanced solid tumors, suggesting the need for alternative targeting strategies.

Sevabertinib in Advanced HER2 -Mutant Non–Small-Cell Lung Cancer

Phase 1-2 study evaluates sevabertinib in advanced HER2-mutated non-small-cell lung cancer, indicating promising outcomes.

OCT 2025JänneNew England Journal of Medicine

Survival with Osimertinib plus Chemotherapy in EGFR -Mutated Advanced NSCLC

Phase 3 trial shows significant overall survival improvement with osimertinib and chemotherapy in EGFR-mutated NSCLC, indicating a promising treatment approach.

Data from Molecular Characterization of NUT Carcinoma: A Report from the NUT Carcinoma Registry

This analysis explores NUT carcinoma fusions and the effectiveness of NGS in diagnosis, suggesting molecular profiling is essential.

Supplementary Figure S1 from Molecular Characterization of NUT Carcinoma: A Report from the NUT Carcinoma Registry

This report illustrates the patient selection process and cohort assignment in the NUT carcinoma registry, showing inclusion and exclusion criteria.

Supplementary Figure S4 from Molecular Characterization of NUT Carcinoma: A Report from the NUT Carcinoma Registry

Supplementary Figure S6 from Molecular Characterization of NUT Carcinoma: A Report from the NUT Carcinoma Registry

Illustrative diagram depicts gene fusion events in NUT carcinoma, suggesting pathways for oncogenic transcription.

Supplementary Figure S5 from Molecular Characterization of NUT Carcinoma: A Report from the NUT Carcinoma Registry

Enrichment analysis reveals key Gene Ontology categories related to co-occurring alterations in NUT carcinoma.