Review Series
Abstract
Cell-cycle dysregulation is a central driver of breast cancer progression and a major therapeutic vulnerability, particularly in hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) disease. The clinical success of cyclin-dependent kinase (CDK) 4/6 inhibitors combined with endocrine therapy has transformed treatment paradigms and established cell-cycle targeting as a cornerstone of care. However, important challenges remain, including hematologic toxicity, incomplete and largely cytostatic responses, and the near-universal development of resistance. These limitations have highlighted the need for next-generation CDK-directed strategies capable of improving selectivity, extending disease control, and overcoming adaptive escape pathways. This Review examines the evolving landscape of CDK-targeted therapeutics in breast cancer, with particular emphasis on emerging CDK4-selective inhibitors, CDK2-directed approaches, and broader multi-CDK strategies. We discuss the biological rationale underpinning these agents, the mechanisms of resistance that have informed their development, and the clinical opportunities they may create across both advanced and early-stage settings. By refining target specificity and addressing resistance-associated cell-cycle rewiring, next-generation CDK inhibitors may reduce toxicity, enhance treatment durability, and enable more effective combination and sequencing strategies. Collectively, these advances promise to move breast cancer treatment beyond current CDK4/6 inhibition toward more precise, adaptable, and durable cell-cycle–directed therapy.
Authors
Daria Seriak, Jun Yong Kim, Geoffrey I. Shapiro, Antonio Giordano
Abstract
Somatic alterations in the phosphoinositide 3-kinase (PI3K) pathway are frequent oncogenic drivers in cancer and are particularly relevant in estrogen receptor–positive breast cancer, where PI3K signaling integrates hormonal, growth factor, and metabolic inputs. Therapeutic targeting of PI3K has been limited by toxicity, pathway crosstalk, and adaptive resistance. Recent advances in structural and functional characterization of PIK3CA mutations have enabled the development of more selective inhibitors, including PI3K isoform–selective and emerging allosteric PI3Ka mutant–targeted compounds. These approaches aim to improve the therapeutic index while maintaining pathway inhibition. In parallel, combination strategies with endocrine therapy and CDK4/6 inhibitors have demonstrated clinical benefit in selected patient populations. However, responses are often transient owing to compensatory signaling and pathway reactivation. Additional metabolic and transcriptional adaptations further contribute to sustaining tumor cell survival. Overall, PI3K-targeted therapy is evolving along two complementary paths: increased mutant-selective inhibition to improve therapeutic index and broader pathway-level strategies designed to overcome adaptive resistance and achieve more durable responses. Ongoing efforts focus on optimizing combination strategies, enhancing development of predictive biomarkers, and improving therapeutic sequencing to achieve durable responses while minimizing toxicity.
Authors
Fabiana Napolitano, Nisha Unni, Carlos L. Arteaga
Abstract
One in eight women will be diagnosed with breast cancer in their lifetime. Most breast cancers express estrogen receptor α (ERα) and depend on its signaling, which promotes tumor growth, survival, and metastatic spread through hormone-dependent transcriptional reprogramming. Selective estrogen receptor degraders/downregulators (SERDs), such as fulvestrant (faslodex), which was FDA approved in 2002, are second-line endocrine therapies for the treatment of advanced metastatic disease. Tumors containing activating hotspot mutations in ESR1 (the gene encoding ERα) retain some sensitivity to fulvestrant but require higher doses to achieve inhibition of the mutant receptor. Substantial efforts to develop next-generation SERDs with improved pharmacology over fulvestrant have led to the FDA approval of the first-in-class orally available SERD elacestrant (Orserdu), followed by imlunestrant (Inluriyo), and the anticipated approval of several more therapies. Excitingly, recent studies show that in addition to their previously described antitumoral mechanisms, SERDs also act by increasing antitumor immunity. In this Review, we detail the current SERD clinical landscape and our emerging understanding of the interplay among SERDs, breast cancer cells, and the tumor immune microenvironment.
Authors
Kristen S. Young, Sean W. Fanning
Abstract
Immunotherapy has revolutionized the therapeutic landscape for many cancers, but its application in solid tumors has lagged. There is now evidence that immunotherapy can improve outcomes in triple-negative breast cancer, but hormone receptor–positive (HR+) breast cancer has traditionally been considered immunologically cold. However, emerging evidence challenges this binary paradigm, suggesting that a biologically relevant subset of HR+/human epidermal growth factor receptor 2–negative (HER2–) tumors exhibit meaningful immunogenic features and clinically relevant sensitivity to immune-based treatment. In this Review we summarize the current understanding of immunogenicity and clinical use of immune-based treatments across breast cancer subtypes. We argue for a broader view of a spectrum of breast cancer immunogenicity and highlight the importance of host factors, including parity and lactation history, in shaping antitumor immunity. Improved identification of immunologically active subsets and deeper mechanistic insight will be essential to expand the therapeutic benefit of immunotherapy to broader patient cohorts and to refine care of patients with breast cancer.
Authors
Jasmine Kay, Julia R. Dixon-Douglas, Michael A. Harris, Courtney T. van Geelen, Sherene Loi
Abstract
Homologous recombination repair deficiency (HRD) occurs in approximately 10% of breast tumors and represents a major targetable vulnerability across multiple cancer types. Impairment of the homologous recombination DNA repair pathway — arising through somatic and germline mutations in homologous recombination repair genes, epigenetic mechanisms, and transcriptomic changes — leads to genomic instability and a reliance on error-prone repair mechanisms. Poly (ADP-ribose) polymerase (PARP) inhibitors harness the synthetic lethality of HRD and PARP inhibition, with current approvals encompassing both early-stage and advanced breast cancer in patients with germline BRCA1/2 (gBRCA1/2) mutations. However, emerging evidence suggests efficacy of PARP inhibitors beyond gBRCA1/2-mutated breast cancer to tumors with other homologous recombination repair defects that confer a “BRCAness” phenotype. This Review examines opportunities to broaden the use of PARP inhibitors in breast cancer and underscores the importance of innovative biomarkers, combination strategies, and next-generation agents to maximize therapeutic impact.
Authors
Charlotte S. Walmsley, Adela Rodriguez, Panagiotis A. Konstantinopoulos, Geoffrey I. Shapiro, Sara M. Tolaney, Judy E. Garber, Filipa Lynce
Abstract
Despite growing recognition of invasive lobular carcinoma (ILC) as a biologically and clinically distinct subtype of breast cancer, ILC remains understudied. Most contemporary therapeutic trials continue to enroll patients predominantly with invasive ductal carcinoma/invasive carcinoma of no special type and rarely stratify by histology. As a result, ILC’s unique disease biology, characteristic loss of E-cadherin function, diffuse growth pattern, and distinct metastatic tropism remain underrepresented in evidence that guides systemic therapy recommendations. In this Review, we examine key molecular alterations and emerging therapeutic targets in ILC, emphasizing recent preclinical discoveries that identify subtype-specific therapeutic vulnerabilities and guide the development of histology-specific treatment approaches for this unique disease. In combination with endocrine therapies, effective targeting in ILC may require a multilayered strategy that extends beyond genomic alterations to leverage ILC’s specific estrogen receptor–associated proteins, metabolism, and tumor microenvironment. Future clinical trial frameworks incorporating prespecified ILC cohorts, tailored endpoints, and coclinical approaches enabling parallel testing in patients and patient-derived models could help accelerate the development and evaluation of ILC-targeted therapeutics.
Authors
Kristina A. Fanucci, Shaymaa Bahnassy, Arya Mariam Roy, Anna Sokolova, Daniel G. Stover, Peter T. Simpson, Rebecca B. Riggins, Rinath Jeselsohn
Abstract
Antibody-drug conjugates (ADCs) have transformed the treatment landscape of breast cancer and redefined the conceptual distinction between targeted therapy and conventional chemotherapy. Originally conceived as “magic bullets” that selectively deliver cytotoxic warheads to antigen-expressing tumor cells, clinical and mechanistic evidence indicates that ADC activity depends on a broader interplay of target-dependent and target-independent mechanisms, including extracellular payload release, bystander killing, off-tumor uptake, and immune modulation. Here, we examine ADCs in breast cancer as a distinct therapeutic paradigm. We discuss how antigen biology, linker chemistry, payload features, and drug-to-antibody ratio collectively determine efficacy, toxicity, and therapeutic index. We then compare currently approved and emerging HER2- and TROP2-directed ADCs, highlighting how differences in linker stability, payload pharmacology, and bystander capacity can affect clinical outcomes in ADCs sharing the same target. We further discuss the biological basis and translational challenges of de novo and acquired resistance related to targets, payloads, and tumor microenvironmental constraints, as well as the implications of these mechanisms for biomarker development, sequencing rationales, and combination strategies with immune checkpoint inhibitors and DNA repair–targeting therapies. Finally, we outline future directions of ADC development, including expansion of the target space, novel payload modalities, and next-generation antibody and conjugation engineering.
Authors
Chenxu Guo, Leif W. Ellisen
Abstract
Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson’s disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin–dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin–dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.
Authors
Bishal Basak, Julia F. Riley, Neha M. Nataraj, Erika L.F. Holzbaur
Abstract
The cGAS/STING pathway is a central innate immune DNA-sensing system that links aberrant DNA species to innate immune and stress-response transcriptional programs and has emerged as a key regulator of tumor-immune interactions. In cancer, pathway outputs are shaped by interconnected downstream signaling modules, including type I IFN, NF-κB, autophagy, and stress-metabolic checkpoints, as well as by stringent spatial and biochemical regulation of both cGAS and STING. When activation is acute and appropriately compartmentalized, cGAS/STING signaling promotes antitumor immunity across multiple cellular compartments in the tumor microenvironment, supporting DC cross-priming and cytotoxic lymphocyte responses. In contrast, chronic or dysregulated activation rewires downstream signaling toward stress-adaptive and inflammatory programs that promote tumor progression, metastasis, and immune dysfunction, including deleterious effects in lymphocytes and the induction of suppressive myeloid and B cell populations. Here, we examine how context determines the consequences of cGAS/STING activation in cancer, review emerging therapeutic strategies that modulate this pathway, and discuss how its antitumor potential can be maximized while minimizing systemic toxicity and immune dysregulation.
Authors
Yi Wang, Juan Angulo-Lozano, Yueqi Wang, Liang Deng
Abstract
Cardiovascular diseases (CVDs) remain the leading cause of mortality and morbidity worldwide, highlighting the need for novel therapeutic approaches. Inflammation plays a key role in CVD pathogenesis, and accumulating evidence has implicated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway in this process. The cGAS/STING pathway recognizes both non-self- and self-DNA, including mitochondrial and nuclear DNA, to activate its downstream proinflammatory signaling molecules, including TANK-binding kinase 1, IFN regulatory factor 3, and NF-κB. Various pathological stressors have been shown to induce self-DNA release into the cytosol and bloodstream from damaged cells in the cardiovascular system, indicating that circulating cell-free DNA is a useful biomarker of CVDs; however, how this contributes to the inflammatory signaling, cell death, and fibrosis that characterize CVDs remains unclear. Here, we discuss the current understanding on the roles of self-DNA and the cGAS/STING pathway in the pathophysiology of CVDs and the therapeutic potential of targeting this pathway.
Authors
Wataru Saitoh, Yasutomi Higashikuni, Oyunbileg Bavuu, Masataka Sata, Daiju Fukuda
No posts were found with this tag.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)