Ovarian cancer (OC) is the eighth leading cause of cancer deaths in women globally, mainly originating from epithelial cells. It is further divided into type-I and type-II based on histology, molecular, clinical, and epidemiological characteristics. OC is commonly diagnosed in postmenopausal women, although this varies by ethnicity and genetics. Non-Hispanic white women have higher rates of OC, while African American women, despite lower incidence, are diagnosed at a younger median age. Family history and BReast CAncer gene 1&2 (BRCA1/BRCA2) mutations significantly correlate with a heightened risk of OC. Obesity, particularly from childhood, is associated with a higher risk of OC. Late menopause and smoking, are linked to a higher risk, especially for mucinous and possibly serous OC. Hormone-replacement-therapy, particularly with unopposed estrogen, also increases the risk of OC. Endometriosis raises the risk for specific subtypes like clear cell and endometrioid carcinoma. Women who have never given birth (null-parity) are at higher-risk for endometrioid and clear cell carcinoma. Surgical resection is crucial for reducing primary and local metastatic disease, involving inspection of the peritoneal cavity, cytology, lymph node removal, and biopsies. The success of surgery is limited by the visibility, extent, and tissue infiltration of the disease. The choice between neoadjuvant-chemotherapy and primary debulking surgery depends on patient health and tumor biology. Secondary cytoreductive surgery may be beneficial for platinum-sensitive recurrent OC. The use of PARP inhibitors and targeted therapies adds complexity to surgical decisions. Ongoing trials and new therapeutic strategies are expected to enhance the management and outcomes of OC.

Abstract Prostate cancer is a predominant cause of cancer related death in men and in most cases, it is difficult to diagnose and adequately monitor. Cancer cells entail targets for effective therapy; however, non-malignant cells do not because they are not expressed in the same way in a cancer cell as in normal cells. RalBP1 functions as a crucial mercapturic acid transporter, playing an essential role in cancer cell survival and therapy resistance. RalBP1 has been identified as the key to radiation and chemotherapy resistance as it is an overexpressed, multi-specific ATP-dependent transporter. Therefore, we investigated its involvement in modulating critical signaling proteins that influence upstream survival pathways and mechanisms responsible for chemo-radiotherapy resistance in prostate cancer. Evidence from in vitro cell cultures and in vivo tumor models suggests that cancer cell survival depends on RalBP1, as its inhibition or depletion results in selective toxicity toward malignant cells. By generating glutathione-electrophile conjugates (GS-Es) within cells, RalBP1 induces apoptosis in cancer cells. In vivo studies revealed that treatment of DU145 prostate cancer xenograft-bearing mice with RalBP1-directed agents; antibodies, siRNA, or antisense oligonucleotides that led to a marked suppression of tumor growth, even in already established subcutaneous tumors, and did so without signs of systemic toxicity. Interestingly, both RalBP1 antibodies, which block RalBP1-mediated transport function, and gene-silencing approaches such as siRNA and antisense, which diminish RalBP1 expression, demonstrate nearly equivalent tumor-regressive effects. This equivalence suggests that disrupting RalBP1 transport function at the cell membrane is sufficient to elicit an anticancer response. Collectively, these findings uncover a novel therapeutic potential for RalBP1 inhibition or depletion in prostate cancer and underscore its promise as a target for new treatment strategies. (This work was supported in part by the Department of Defense grant HT9425-25-1-0500. Funding from the Beckman Research Institute of City of Hope is also acknowledged). Citation Format: Sharad S. Singhal, Madhu Krishna, Prakash Kulkarni, David Horne, Ravi Salgia. RalBP1 inhibition: A novel therapy for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7127.

Background: Gynecological cancers include collections of cancers with diverse cellular and molecular characteristics that often develop drug resistance, making them treatment-resistant. Biomolecule-drug conjugates (BDCs), especially antibody-drug conjugates (ADCs), have revolutionized the targeted therapy of cancer; however, the creation of these entities has so far been achieved by empirical, resource-intensive design methods. Objective: The aim of this review is to critically analyze how AI can be used for the rational design and optimization of high-affinity BDCs for gynecological cancer treatment. Methods and discussion: Recent advances in machine learning (ML)- and deep learning (DL)-based methods to predict biomolecule-target binding affinity, structural compatibility, linker stability, payload selection, trafficking in the cell, and biomolecule resistance mechanisms are summarized. The review also explores the possibilities for incorporation of structural, chemical, biological, and multi-omics data to enhance specificity, efficacy, and safety of conjugates. Besides antibody-based systems, AI-assisted design approaches with peptides, aptamers, and hybrid biomolecular systems are also included. This review also highlights parameters and experimental/numerical validation restrictions related to data quality, interpretability of models, regulatory aspects, etc. Conclusions: AI-based conjugate engineering is increasingly moving BDC development from a largely 'trial and error' approach to a more predictive and data-driven approach. While there are still challenges to be addressed in terms of translations and validations, the potential of AI approaches in the field of precision oncology and the development of more personalized treatment is promising in the context of gynecological cancers.

Gene regulatory network models treat interaction parameters as fixed, although regulatory efficacy fluctuates. We asked how temporal fluctuations in interaction strength reshape phenotype occupancy in cell-fate decision GRN motifs. Across large parameter ensembles, anchored fluctuations largely preserved deterministic occupancies. Additive fluctuations increased occupancy of all-high co-expression states, particularly where high expression was accessible. In contrast, multiplicative fluctuations biased inhibitory interactions toward stronger repression and favored single-high states in a topology-dependent manner. Deterministic controls sampled from noise-induced parameter distributions did not fully reproduce these effects. A Boolean-limit analysis revealed an intrinsic upward bias: loss of repression increased expression regardless of regulator state, whereas stronger repression acted only when the regulator was present. Analyses of epithelial-mesenchymal plasticity and gonadal-fate networks showed increased occupancy of hybrid team-expression states under additive fluctuations. Thus, regulatory noise can reshape the developmental landscape in opposing directions, pushing cell-fate systems toward either progenitor-like or terminally differentiated states.

Abstract Ovarian tumor metastasis is a leading cause of cancer-related deaths worldwide. Ovarian cancer (OC) cells frequently metastasize to the peritoneum. OC cells, after detaching from the primary tumor, can float in the ascitic fluid (fluid that accumulates in the abdominal cavity due to cancer) and attach to the peritoneum, the lining of the abdominal cavity. Peritoneal metastasis is strongly linked to poor prognosis in OC patients. In the current study, we evaluated the anti-proliferative and anti-metastatic effects of RLIP inhibition in an array of OC cell lines and an orthotopic mouse model of ovarian metastasis. Compared to control treatment, RLIP inhibition and/or depletion reduced in-vitro cell viability and suppressed the migratory and invasive potential of OC cells. Further, mice intraperitoneally implanted with luciferase-expressing HeyA8 OC cells were treated with RLIP antisense (RAS; 4 mg/kg, b.w.), RLIP antibody (Rab; 4 mg/kg, b.w.) or a combination of RAS+Rab. RAS-, and Rab-treated mice exhibited significantly lower primary tumor weight and reduced metastasis compared to control mice. Mice treated with a combination of RAS+Rab exhibited no metastasis and significantly lower tumor weight than the single agent-treated mice. In-vivo studies showed that the RLIP targeting agent's treatment prolonged the survival of NSG mice inoculated with HeyA8-luc OC cells. Collectively, our results suggest that RLIP antisense has potential to be combined with RLIP antibodies to more effectively suppress primary ovarian tumor growth and metastasis to the peritoneum that warrants further investigation. (This work was supported in part by the Department of Defense grant W81XWH-22-1-0331. Funding from the Beckman Research Institute of City of Hope is also acknowledged). Citation Format: Sharad S. Singhal, Madhu Krishna, Prakash Kulkarni, David Horne, Ravi Salgia. RLIP depletion suppresses ovarian cancer growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1807.

One of the leading causes of cancer deaths worldwide is ovarian tumor metastasis. It is very common for ovarian cancer (OC) cells to metastasize to the peritoneum. Free-floating OC cells can drift in the ascitic fluid (fluid that accumulates in the abdominal cavity due to cancer) and attach to the peritoneal lining of the abdominal cavity. In OC, peritoneal metastasis is strongly associated with poor prognosis. This study compared the effects of RLIP inhibition in various OC cell lines and in an orthotopic mouse model of ovarian metastasis to assess its anti-proliferative and anti-metastatic activity. Relative to the control treatment, RLIP inhibition and/or depletion decreased in vitro cell viability and minimized migratory and invasive capabilities of OC cells. The in vivo model was performed using HeyA8 OC cells expressing the luciferase gene that were implanted into the mice followed by the treatment of the mice with RLIP antisense (RAS, 4 mg/kg, b.w.), RLIP antibody (Rab, 4 mg/kg, b.w.) and a combination of RLIP antisense and RLIP antibody (RAS + Rab). Primary tumor weight and metastatic lesions were reduced in both RAS-treated and Rab-treated mice compared to control mice. Mice that received the RAS + Rab combination had almost no metastasis, and their tumor weight was much lower than that seen with either agent alone. Survival was also extended in NSG mice inoculated with HeyA8-luc OC cells when treated with RLIP-targeting agents. Overall, our findings indicate that RLIP antisense together with RLIP antibodies may be effective in controlling primary tumor growth and peritoneal metastasis, supporting the need for continued investigation. Key findings of this study with potential clinical relevance include: • RLIP is an attractive therapeutic target with the ability to suppress human OC at multiple stages of development. • Reducing RLIP levels significantly inhibits OC cell growth and enhances apoptosis compared with controls. • RLIP blockade/depletion may serve as a broad-spectrum therapeutic strategy that remains effective regardless of common pathway differences among OC subtypes. • This is the first evidence from integrated in vitro and in vivo studies demonstrating the strong therapeutic promise of RLIP-targeting agents for treating metastatic OC.

The most difficult hurdles associated with the treatment of gynecologic cancer (such as ovarian, cervical, and endometrial cancer) is chemoresistance, with ovarian cancer representing the most clinically challenging subtype due to frequent relapse and the development of platinum resistance. Although chemotherapy remains one of the most important approaches to the management of gynecologic cancer, a large portion of patients have a poor initial response or recurrence of the treatment-resistant disease, factors that influence the rate of survival. This review highlights the present understanding of biological, molecular, and micro-environmental mechanisms that cause chemoresistance in gynecologic cancers, with primary emphasis on ovarian cancer while drawing supportive comparisons with cervical and endometrial malignancies. Important mechanisms of chemoresistance like increased drug efflux, redox based detoxification, increased capability of repairing DNA, evading apoptosis, protection by tumor microenvironment, epithelial-mesenchymal transition, persistence of cancer stem cells, epigenetic reprogramming and exosome-based communication are discussed in an integrated and easily understandable style. In addition to the overview of these mechanisms, this review also brings out newer treatment approaches that may emerge to overcome drug failure, especially in platinum-resistant ovarian cancer. These approaches include drug efflux transporter inhibitors, redox and metabolic pathways modulators, DNA repair, epigenetics, immunotherapies, tumor microenvironment, nanotechnology-delivery systems, and exosome interventions. The development in artificial intelligence and multi-omics methods that can be used to predict treatment response and deliver personalized management are also discussed, highlighting their potential role in early identification of resistance and treatment stratification in ovarian cancer patients. Collectively, these insights may help to improve therapeutic decision-making, which could enhance chemotherapy responsiveness, and support durable clinical outcomes in ovarian and other gynecologic malignancies.

Acquired resistance to osimertinib remains a major barrier in EGFR-mutant lung adenocarcinoma (LUAD), and in many patients cannot be explained by secondary targetable mutations. This pattern highlights a central role for non-genetic plasticity programs, including epithelial-mesenchymal transition (EMT), drug tolerance, immune evasion, and lineage switch. Here, we used a systems-level framework to define how these processes are coordinated. We constructed a minimal gene regulatory network integrating core EMT regulators with AXL, RB1, PD-L1, and NF-κB, and analysed its emergent behaviour using dynamical simulations. The network resolved into two mutually inhibitory, self-reinforcing "teams": an epithelial/sensitive team centred on RB1, miR-200, miR-34, p53, and E-cadherin, and a mesenchymal/resistant team centred on ZEB1, SNAIL, AXL, PD-L1, and NF-κB. Simulations predicted a strong coupling between EMT and osimertinib resistance, which was validated across bulk transcriptomic datasets from NSCLC cell lines, EGFR-mutant patient cohorts, and perturbation experiments. Inducing EMT increased RB1-loss programs, whereas osimertinib exposure induced AXL and EMT programs, supporting bidirectional regulation and reinforcement. Single-cell and spatial transcriptomic analyses further showed that EMT, AXL, PD-L1 activity, and reduced RB1 signaling co-occur within tumors. Clinically, activation of individual axes such as EMT, RB1 loss, or PD-L1 upregulation was associated with worse outcomes, while combined activation produced markedly poorer survival than any single axis alone. Extending the network to incorporate lineage regulators further linked a partial LUAD-to-LUSC shift with EMT, RB1 loss, and resistance. Together, these findings identify a network topology that coordinates multiple plasticity programs driving osimertinib resistance and suggest that disrupting this cooperative architecture may offer a therapeutic strategy in EGFR-mutant LUAD.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and patient outcomes have remained largely unchanged despite advances in multimodal therapy. Immune checkpoint inhibitors (ICIs), which block the PD-1/PD-L1 axis to restore T cell-mediated anti-tumor immunity, have emerged as a promising treatment strategy. However, response rates remain below 20% in HNSCC, underscoring the need to better understand mechanisms of immune evasion within the tumor microenvironment. Syngeneic mouse models are essential for studying tumor-immune interactions, yet currently available HNSCC models are limited. Here, we report the development of a novel FVB/NJ-derived syngeneic HNSCC model generated from 7,12-dimethylbenz(a)anthracene (DMBA)-induced primary on floor of mouth/buccal tumors, designated FMOC1, FMOC2, and FMOC3 ( F VB/NJ M ouse O ral C ancer). In vitro , all FMOC cell lines exhibited robust proliferative capacity with distinct proliferation kinetics. In vivo , all FMOC cell lines exhibited characteristic HNSCC histopathology, including cytokeratin 5 positivity, and were tumorigenic in immunodeficient NCG mice; however, in syngeneic immunocompetent mice, only FMOC1 demonstrated sustained tumor growth at orthotopic and flank sites, whereas FMOC2 and FMOC3 tumors underwent spontaneous regression within 2 weeks, indicating differential immune-dependent tumorigenicity among the lines. Consistent with this, depletion of CD4+ and/or CD8+ T cells restored tumor growth in FMOC2 and FMOC3 models, indicating a critical role for T cell-mediated immunity in tumor suppression. Notably, FMOC1 tumors were responsive to anti-PD-L1 and anti-CTLA-4 therapy, supporting their utility for evaluating immunotherapeutic strategies. Collectively, these findings establish the FMOC model as a novel and versatile platform to study tumor-immune interactions and immune evasion mechanisms in HNSCC, with potential applications in preclinical immunotherapy development.

Background: A 71-year-old female never-smoker, with a remote history of secondhand smoke and a medical history including hyperlipidemia, hypertension, fatty liver, and chronic thrombocytopenia. Additionally, her family history is significant for multiple first-degree relatives with malignancy, including a father with lung cancer. Case Description: An initial abdominal ultrasound revealed multiple hepatic lesions concerning for metastatic disease. Further imaging revealed a right upper lobe lung mass with hepatic, osseous, and craniofacial metastases, including calvarial and right masticator space lesions with epidural extension. A biopsy confirmed adenocarcinoma with an EGFR exon 19 deletion (p.E746_P753delinsVS). The final clinical stage was assigned as stage IVB cT3N3M1c. Prior to systemic therapy, a total dose of 30 Gray using stereotactic body radiation therapy was delivered to the right maxilla and skull base for local control. The patient was then initiated on combination therapy with carboplatin (area under the curve 5), pemetrexed (500 mg/m2), and osimertinib (80 mg), completing six cycles. Maintenance therapy with pemetrexed and osimertinib was initiated thereafter and is ongoing. Follow-up imaging revealed interval reduction of the primary lung mass, pulmonary nodules, and hepatic metastases, along with increased sclerosis of osseous lesions, resolution of the epidural extension, and improvement in the right masticator lesion. Conclusions: The treatment has been well tolerated, with sustained clinical and radiographic responses. Although limited to a single case, our findings support the growing interest in combining systemic and local therapies in EGFR-mutant non-small cell lung cancer and offer a potential framework for adapting these strategies to molecularly analogous tumors. Longer-term follow-up and further studies are needed to refine patient selection and optimize treatment intensity.

Tumor heterogeneity and evolution constrain NSCLC immunotherapy, leading to variable and often short-lived responses. This commentary discusses the ARPA-H ADAPT program and IMMUNO-BIOMAP trial, which longitudinally profile tumors and the microenvironment to identify resistance mechanisms in real time and enable adaptive, biomarker-guided, personalized treatment strategies.

9552 Background: Lifileucel (Amtagvi), an autologous tumor-infiltrating lymphocyte (TIL) therapy, was FDA approval for unresectable or metastatic melanoma after progression on systemic therapy based on clinical trial data. However, real-world data describing early outcomes with lifileucel remain limited. Methods: We retrospectively reviewed a prospectively maintained database of patients with unresectable/metastatic melanoma who progressed on immune checkpoint inhibitors (and BRAF ± MEK therapy if applicable) and received lifileucel per standard protocol at a single institution April 2024–January 2026. Eligible patients received an in-specification TIL product and had evaluable imaging ≥12 weeks post-infusion unless progression was detected sooner. Responses were assessed per RECIST v1.1. Endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and grade ≥3 treatment-related adverse events (TRAEs), excluding lymphodepletion-related cytopenias. Time-to-event endpoints were estimated using Kaplan–Meier methods. Results: Of 38 patients who underwent surgical TIL harvest, 32 (84%) received lifileucel, including 5 via the Expanded Access Program due to out-of-specification product. Among 27 patients receiving in-specification lifileucel, 20 had evaluable imaging and were included in the analysis. Patients received a mean of 2.2 prior therapies, and 35% had acral lentiginous or mucosal melanoma. All patients had Stage IV disease, including liver (40%) and brain (30%) metastases. 55% received bridging therapy after surgery prior to infusion. Median follow-up was 5.7 months (range, 0.9–16.9). ORR was 30% (3 CR, 3 PR), and DCR was 45%. Among responders, 67% (4/6) have ongoing response and median DoR was not reached. Median PFS was 3.5 months (95% CI, 2.1–5.3) and median OS was 6.1 months, with 6- and 12-month OS rates of 51% and 44%, respectively. Non-cytopenic grade ≥3 TRAEs occurred in 55%. Conclusions: In this early real-world experience, lifileucel demonstrated encouraging antitumor activity with ongoing responses in heavily pretreated patients despite high-risk features such as elevated LDH and liver and brain metastases. Additional studies and longer follow-up are warranted to optimize patient selection and define durability of benefit and survival outcomes. Baseline patient characteristics and safety outcomes. Characteristic/Outcome Overall (N=20) Age, median (range), y 62 (38-80) Male sex, n (%) 12 (60) Acral lentiginous/mucosal subtype, n (%) 7 (35) BRAF V600E mutation, n (%) 4 (20) LDH level > ULN, No. (%) 5 (25) Liver Metastases, No (%) 8 (40) Brain Metastases, No (%) 6 (30) Prior systemic therapies, mean (range) 2.2 (1-5) Patients with grade ≥3 non-hematologic TRAEs, n (%) 11 (55)

The advancement of mRNA technology has rejuvenated the cancer treatment immunotherapy field by providing a flexible and scalable platform to generate tumor-associated or patient-specific neoantigens, which induces strong cytotoxic and helper T-cell outcomes and also immunologically stimulates innate immunity in the body at the same time. In contrast to conventional vaccines, mRNA preparations are non-integrative, safe, and scalable, allowing personalization of mutational landscape-based vaccines much faster due to the unique mutations of tumors in individuals. Early clinical trials in melanoma, breast, glioblastoma, and pancreatic cancer have revealed encouraging immunogenicity results, especially when used along with checkpoint inhibitors or other complementary therapies. The recent news of discovering the mRNA cancer vaccine, Enteromix, in Russia, also points to the potential of the translation and the global trend of this technology, which is both effective in treatment and accessible in clinical practice. Although the issues such as heterogeneity of the tumors, antigen escape, delivery efficiency, and manufacturing logistics are present, the development of artificial intelligence, multi-omics integration, and next-generation delivery systems will address these challenges. This review gives an overview of the concepts and principles, types, delivery mechanisms, clinical applications, and future perspective of mRNA-based cancer vaccines with a focus to its revolutionary contribution to personalized oncology and the overall next-generation immunotherapy.

Acute myeloid leukemia (AML) is characterized by poor survival, especially in older patients with relapse/refractory disease. With an apparent lack of reliable long-term treatments, pathways involved in chromatin regulation represent potentially leverageable targets. The arginine methyltransferase CARM1 is a known dependency in AML, yet clinical grade inhibitors have remained elusive. We found that CARM1 promotes DNA repair and other pathways associated with malignant growth. Dysregulation of DNA repair pathways is pervasive in AML and linked to the transforming phenotype. Interestingly, targeting CARM1 chemosensitized AML cells for DNA-PK inhibition by peposertib, thereby blocking NHEJ (non-homologous end joining). Also, H3K27ac (histone H3 lysine 27 acetylation) active enhancer marks and marks of the corresponding histone acetyl transferase, P300, were found at the promoter region of relevant CARM1-regulated DNA repair enzymes. Consequently, our results show that CARM1 dependencies could also be exploited by utilizing inobrodib, a p300/CBP bromodomain inhibitor that synergizes with peposertib treatment in AML cells. Overall, these data demonstrate a rational approach for combination therapy by exploiting dependencies through inhibition of proximal effector function in addition to essential NHEJ repair, targeting its rate-limiting enzyme complex, thereby resulting in synergistic inhibition in primary AML.

Abstract Purpose Comprehensive genomic profiling (CGP) has changed the treatment paradigm for non-small cell lung cancer (NSCLC) with the advent of molecularly targeted therapies for actionable genomic alterations (AGA). Despite this, the use of CGP is suboptimal, particularly in squamous cell lung cancer (sqNSCLC), which is more closely associated with smoking exposure and a lack of AGAs. We hypothesized that the prevalence of AGAs is inversely correlated with the chronicity and extent of smoking exposure in patients with sqNSCLC. Experimental Design We retrospectively evaluated all patients with liquid biopsy testing via Guardant 360CDX or Guardant360 in the context of any sqNSCLC diagnosis at the City of Hope Comprehensive Cancer Center between 10/2020 and 7/2023. The data was obtained on 2/23/24. Social and clinical histories were evaluated to assess the frequency of AGAs in patients with no or remote smoking history. Results Of the 56 patients in the initial evaluation, 24% (n=13) were non-smokers or remote smokers (greater than 20 years from cessation). Of these 13 patients, eight (61.5%) harbored AGA. Of these 8 patients, alterations observed included EGFR exon 19 deletion (50%, n=4), MET exon 14 skipping mutation (25%, n=2), EGFR G719S (13%, n=1), EGFR E114K (13%, n=1). Of those patients harboring AGAs that received NCCN-concordant matched targeted therapy, the objective response rate (ORR) with targeted agents was 50% and the clinical benefit rate (CBR) was 83.3%. Conclusions These data support the use of CGP in sqNSCLC particularly in patients with remote or no smoking exposure. Statement of translational relevance These data demonstrate high frequency of actionable genomic alterations (AGAs) in patients diagnosed with squamous cell lung cancer (sqNSCLC) with remote or no smoking history. Specifically, enrichment of EGFR and MET gene alterations were observed. These findings support the use of comprehensive molecular profiling in sqNSCLC. Furthermore, treatment outcomes demonstrate frequent objective responses and high clinical benefit rate supporting the use of targeted therapies in sqNSCLC harboring AGAs. This analysis provided rationale for further research of larger datasets investigating therapeutic approaches in sqNSCLC, which may have significant implications for consensus guideline recommendations and routine clinical practice.

Anaplastic lymphoma kinase (ALK) rearrangements define a distinct molecular subset of non-small cell lung cancer (NSCLC) that is highly sensitive to ALK tyrosine kinase inhibitors (TKIs). While canonical EML4::ALK fusions are well characterized, the clinical significance of rare noncanonical ALK rearrangements and structural alterations remains incompletely understood and may present interpretive challenges across sequencing platforms. Here, we present the case of a 61-year-old never-smoker with metastatic lung adenocarcinoma harboring a rare ALK structural deletion identified through complementary genomic profiling. Initial comprehensive genomic profiling identified an EML4::ALK rearrangement, while subsequent orthogonal DNA/RNA genomic based profiling identified a rare WDR43::ALK structural deletion resulting in a fusion transcript. ALK immunohistochemistry demonstrated ALK protein expression, supporting oncogenic ALK pathway activation despite the atypical genomic architecture. The patient was treated with frontline alectinib and achieved a rapid, deep, and durable response with sustained systemic and intracranial disease control for more than six years. This case highlights the importance of integrative genomic interpretation in precision oncology and supports that rare ALK structural alterations may retain clinically meaningful sensitivity to modern ALK inhibition. As comprehensive sequencing becomes increasingly incorporated into routine oncologic practice, correlation of genomic findings with protein expression, clinicopathologic features, and treatment response may help determine the therapeutic relevance of unconventional ALK alterations.

Breast and ovarian cancers are still one of the most prevalent causes of cancer death among the women in all parts of the world, mostly occurring at a later stage with high recurrence rate and resistance to treatment. Beyond the well-known genetic and epigenetic modifications, the new branch of study is epitranscriptomics that investigates reversible chemical modifications of RNA has brought a new aspect of cancer regulation to light. Modifications such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), pseudouridine (Psi), and N1-methyladenosine (m1A) have dramatic effects on RNA stability, splicing, localization, and translation, which alter oncogenic signalling, immune evasion, and drug resistance. Reprogramming of the transcriptome and proteome with dysregulation of the respective corresponding writers, erasers, and readers of these RNA scripts, enhance tumor proliferation, epithelial-mesenchymal transition (EMT), angiogenesis, and metastasis. Recent developments highlight the putative clinical value of targeting RNA modifying enzymes using small-molecule inhibitor, CRISPR-based editing technology, and delivery systems based on nanotechnology. In addition, RNA modification patterns are emerging as promising diagnostic and prognostic biomarkers, with growing applications in liquid biopsy and precision oncology. A combination of epitranscriptomic data and multi-omics solutions, artificial intelligence (AI), and personalized medicine frameworks offers an effective way of optimizing cancer classification and treatment. This review highlights, how decoding of epitranscriptomic signatures of malignancy can help transform the concept of tumor biology and provide with new avenues of diagnosis, prognosis, and targeted therapy options of breast and ovarian malignancies, representing a new era of patient-centred oncology.

Immune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment; however, durable responses occur in only a subset of patients, underscoring the need for robust predictive biomarkers. Serine/threonine kinase 11 (STK11) is an emerging biomarker that portends poor prognosis and predicts therapeutic resistance. Loss of STK11 disrupts AMPK signaling, leading to unchecked mTOR activation, metabolic reprogramming, angiogenesis, and epithelial-mesenchymal transition, fostering tumor progression and immune evasion. STK11 mutations frequently co-occur with KRAS and KEAP1 alterations, exhibit low PD-L1 expression, an immunosuppressive tumor microenvironment that leads to the development of PD-1/PD-L1 resistance. Clinical studies consistently demonstrate inferior outcomes with ICIs in STK11-mutant NSCLC, particularly in the presence of KRAS and KEAP1 co-mutations. Dual checkpoint inhibition combining PD-1/PD-L1 and CTLA-4 blockade shows promise in overcoming resistance, results remain inconsistent, and prospective trials are ongoing. Beyond immunotherapy, STK11 mutations confer poor outcomes across targeted therapies, including KRAS G12C inhibitors, with KEAP1 co-mutation serving as a strong negative predictor of efficacy. In this review we present an overview of STK11 function and its role in tumor biology, highlight the prognostic and predictive potential of STK11 mutations in the context of NSCLC treatment and summarize the emerging treatment strategies.