Rekha Rani Kokkanti

Poly (ADP-ribose) polymerase inhibitors (PARPi) have transformed the treatment landscape for homologous recombination-deficient (HRD) cancers, particularly those harboring BRCA1/2 mutations, including breast, ovarian, prostate, and pancreatic cancers, by exploiting the synthetic lethality induced by HR deficiency (HRD) and utilizing HRD status as a predictive biomarker. Nevertheless, intrinsic as well as acquired resistance limits their long-term effectiveness. Resistance often develops as a result of several complex mechanisms including the restoration of homologous recombination (HR), stabilization of the replication fork, enhanced drug efflux, loss of PARP1 expression, epigenetic modifications, and changes in the DNA damage response signaling. BRCA1/2-mutant cells, deficient in HR, become reliant on alternative repair pathways like classical non-homologous end joining (c-NHEJ) and microhomology-mediated end joining (MMEJ). Emerging evidence indicates the importance of replication-induced gaps in single-stranded DNA (ssDNA) and alternative pathways of DNA repair in defining PARPi sensitivity and resistance. This review aims to provide a comprehensive analysis of the established and emerging molecular mechanisms of PARPi resistance, and compensatory DNA repair pathways such as MMEJ. In addition to highlighting resistance pathways, the review also discusses strategies focusing on targeting repair mechanisms and replication stress signaling by using novel drugs targeting DNA polymerase theta (POLQ). It subsequently discusses preclinical advancements and ongoing clinical trials. Through linking the molecular determinants of resistance to the translational status and limitations of the latest therapies, this review offers a comparative framework for understanding resistance mechanisms and strategies to restore PARPi sensitivity in cancers with HRD.

Tumor progression and therapeutic failure are classically interpreted through the lenses of genetic evolution and ongoing signaling dynamics. However, increasing evidence suggests that tumors are also shaped by durable imprints of prior microenvironmental exposures. These prior exposures can leave persistent epigenetic and structural imprints that progressively stabilize adaptive cellular states, allowing transient responses to become durable regulatory programs. Chronic inflammation, metabolic stress, therapeutic pressure, and extracellular matrix remodeling induce persistent molecular states across cancer cells and stromal compartments, generating history-dependent phenotypes that influence future biological responses. Building on these observations, we propose that these adaptive processes collectively constitute a distributed tumor microenvironment (TME) memory encoded across cancer cells, fibroblasts, immune cells, endothelial cells, and the extracellular matrix (ECM), rather than representing isolated mechanisms of adaptation. We examine how TME memory contributes to therapy resistance, immune dysfunction, cancer-cell dormancy, minimal residual disease, and tumor recurrence, and discuss the molecular mechanisms underlying memory encoding, persistence, and recall. Finally, we discuss the experimental and clinical strategies required to identify memory-rich tumors, develop biomarkers of historical imprinting, and design memory-aware therapeutic interventions. By integrating diverse forms of adaptive persistence within a unified history-dependent framework, TME memory provides a conceptual foundation for investigating tumor evolution, therapeutic resistance, and future precision oncology strategies.

Head and neck squamous cell carcinoma (HNSCC) continues to pose a major global health challenge, with over 600,000 new cases diagnosed annually and persistently poor survival outcomes despite advances in surgery, radiotherapy, and immunotherapy. Growing evidence implicates metabolic reprogramming, including enhanced glycolysis, glutaminolysis, lipid synthesis, and one-carbon/redox flux as a central driver of HNC initiation, progression, and therapy resistance. In contrast, metabolic crosstalk within the hypoxic, acidic tumor microenvironment (TME) further shapes immune evasion and stromal support. Recent innovations in mass spectrometry platforms (LC-MS, GC-MS, NMR) have attracted attention in clinical therapeutics, and spatial metabolomics imaging techniques now enable high-resolution in situ mapping of metabolites, revealing intratumoral heterogeneity and offering new insights into tumor-immune–stromal interactions and potential biomarkers for precision oncology. In this review, we integrate critical methodological considerations from sample collection and data-analysis workflows to analytical pitfalls with a balanced, pathway-focused analysis of HNSCC dysmetabolism, examine tumor immune stromal metabolic interactions, and highlight translational opportunities through emerging biomarkers, targeted inhibitors, and cutting-edge approaches such as single-cell and AI-driven metabolomics to chart a roadmap toward precision oncology for HNSCC.

Several plants have been studied to find their efficacy and anti-cancer activity in various cancers by synthesizing organic metal nanoparticles. However, usage of Semecarpus anacardium (SA) and production of green synthesized nanoparticles have not been exposed. In our study we have focused on synthesizing silver nanoparticles using the nut extracts from SA. Characterization studies including UV-Visible spectrophotometry have confirmed the silver nanoparticle formation at 412 nm using 0.1 mM and 427 nm using 0.2 mM AgNPs. Particle size was recorded at 1.4 nm confirming their effectivity and zeta potential studies confirmed the respective charge of -38.6 mV of the particle. Anti-microbial activity was shown against gram negative bacteria. MTT assay studies confirmed the anti-cancer activity against ovarian cancer cell line, PA-1. These results depict the excellent cytotoxic effect on the PA-1 ovarian cancer cell line, with an IC50 value of 250 μg/ml. Flow cytometry studies confirmed that SA methanolic nut extracts inhibited cell cycle at G0/G1 phase and induced apoptosis. Taken together, we are confirming that SA methanolic extracts have anti-cancer properties against ovarian cancer cell line, PA-1.