p53 is a transcription factor that functions as a tumor suppressor and the active unit of which is a tetramer. Nearly all cancers inactivate the p53 pathway, primarily through missense mutations in TP53. Most mutant p53 proteins lose their function and often exhibit increased protein stability. In addition to this loss of function, mutant p53 can drive oncogenicity through a dominant-negative effect

Solid cancers are complex ‘ecosystems’ comprised of diverse cell types and extracellular molecules, where heterotypic interactions significantly influence disease etiology and therapeutic response. However, our current understanding of tumor microenvironments (TMEs) remains incomplete, hindering the development and implementation of novel TME-targeted drugs. To maximize cancer therapeutic development

The gut microbiome has emerged as a key regulator of response to cancer immunotherapy. However, a better understanding of the underlying mechanisms by which the microbiome influences immunotherapy is needed to identify strategies to optimize outcomes. To this end, we developed a mathematical model to obtain insights into the effect of the microbiome on the immune system and immunotherapy response.

The arginine methyltransferase CARM1 is amplified/overexpressed in a variety of cancers, including triple-negative breast cancer (TNBC), spurring the interest of developing CARM1 inhibitors (CARM1i). Here, we discovered that CARM1i treatment leads to elevated CARM1 levels as well as activation of AKT, which could result in long-term treatment resistance in breast cancer cells. CARM1 methylated MAP2K4

The 5-year overall survival rate for pancreatic cancer remains ~13%, underscoring the urgent need for improved treatment strategies. TGFβ is a promising target due to its significant involvement in the desmoplasia, immune suppression, and chemoresistance characteristic of pancreatic cancer. Over 300 clinical trials targeting TGFβ have been conducted in unselected patient cohorts; however, none of the

Diffuse midline gliomas (DMGs) are devastating brain tumors that occur primarily in children. The salient feature of these tumors is the presence of a H3K27M mutation (K27M), associated with the worst prognosis. Development of effective strategies for treating K27M+ DMG is desperately needed to help improve patient outcomes. Here, we identified the cell surface antigen CD99 as notably expressed in

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, deadly form of ovarian cancer that uniformly harbors mutations in SMARCA4, a member of the SWI/SNF chromatin remodeling complex. SWI/SNF impacts RNA splicing, and dysregulation of splicing can generate immunogenic tumor antigens. Here, we explored the relationship between SMARCA4 loss and RNA splicing dysregulation. SCCOHT primary

Background: Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing EGFR, thereby limiting associated toxicities. Zongertinib was granted Fast Track and Breakthrough Therapy Designations by the FDA for patients (pts) with advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 mutations and who have received

FAP (Fibroblast Activation Protein) is expressed on cancer-associated fibroblasts (CAFs) and is a highly attractive target in Radioligand Therapy (RLT) due to its pan cancer potential. The penetrating nature of β radiation is hypothesized to drive a ‘cross-fire effect’ from CAFs to tumor cells resulting in DNA damage and tumor cell death. Known FAP targeting ligands show excellent and selective tumor

Background: Cancer cachexia, a metabolic disorder marked by severe muscle loss and common among certain types of cancers, significantly impacts prognosis and quality of life in patients. A core feature of cachexia is skeletal muscle mass reduction, which can be efficiently monitored by assessing the skeletal muscle area (SMA) in computed tomography (CT) scans routinely performed in cancer care. However

HER2 is overexpressed in breast, gastric, and other cancers, with limited expression in normal tissues. Impactful HER2-targeted therapeutics include monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates. However, resistance remains an issue. Bispecific antibody T cell engagers (TCEs) have unrealized potential as novel treatments for solid tumors, with notable past successes

Hepatocellular carcinoma (HCC) is the most common form of liver cancer ranking sixth among all cancers and the third leading cause of cancer death worldwide in 2020. Despite the advent of systemic therapies with tyrosine kinase and later immune checkpoint inhibitors, the prognosis of patients with HCC is still dismal and therefore new more effective therapies are needed. Glypican-3 (GPC3) is an oncofetal

RO7567132 is a novel bispecific antibody that binds bivalently to the lymphotoxin beta receptor (LTBR) and monovalently to the fibroblast activation protein (FAP). LTBR is a member of the tumor necrosis factor receptor superfamily, expressed by various cells including stromal cells. Activation of LTBR upon engagement with its ligands leads to the upregulation of genes involved in the attraction of

Large scale genome wide CRISPR screens identified WRN helicase as a promising synthetic lethal target for MSI-H cancers, independent of tumor type. Here we describe the discovery of the novel clinical WRN helicase inhibitor GSK4418959 (IDE275), which recapitulates the MSI-H synthetic lethality of WRN genetic inhibition in vitro and in vivo. GSK4418959 (IDE275) engages a unique allosteric site in the

Relapsed/refractory (R/R) AML is associated with poor outcomes. Preclinical studies have shown that SENTI-202, a first-in-class CAR NK cell therapy, selectively kills AML blasts and leukemia stem cells (LSCs) while sparing hematopoietic stem & progenitor cells (HSPCs) via its Logic Gated CAR design (Kaveri, 2024). Here, we report interim clinical trial data in patients with R/R AML who received SENTI-202

Background: Development of acneiform rash in patients with colon cancer treated with anti-EGFR therapies frequently results in dose attenuation or discontinuation, thereby limiting benefits. BRAF inhibitors block the MAPK pathway in BRAF V600 mutant cells, while they paradoxically activate the MAPK pathway in BRAF wild type cells. We hypothesized that a topical formulation of a BRAF inhibitor (LUT014

Background: Circulating tumor (ctDNA) for detection of minimal residual disease (MRD) in colorectal cancers is prognostic, however, many cancers are not detected prior to clinical recurrence. Chemotherapy and surgery may limit detection of ctDNA due to increased shedding of DNA. We are exploring the use of an ultra-sensitive MRD assay (NeXT Personal®) in a prospective study of colorectal cancers (VICTORI)

Prostate cancer is the second leading cause of male cancer deaths in the US. There is currently no curative therapy available for advanced prostate cancer, indicating an urgent need for novel therapeutics. ABBV-969 is intended to address this critical need by delivering cytotoxin to tumor cells highly expressing prostate tumor antigens, STEAP1 (six transmembrane epithelial antigen of the prostate-1)

Background: In resource-limited settings, cancer diagnosis is often challenging due to a shortage of expert pathologists. Early and precise diagnosis is vital to enhancing treatment outcomes and reducing morbidity of patients. This issue is particularly prevalent in regions like Bangladesh, where high levels of arsenic exposure increase the risk of non-melanoma skin cancer (NMSC). Here, we assess the

Prostate cancer is the second most commonly diagnosed cancer in men, with 1 in 8 men being diagnosed with prostate cancer in his lifetime. AR is a hormone-activated transcription factor that promotes cell growth and survival in the normal prostate, and AR signaling is a key driver of cell proliferation in prostate cancer. Inhibition of AR signaling is a mainstay of current prostate cancer treatment

The small GTPase KRAS is frequently mutated in cancer and KRASG12D is its most common mutation, with ∼34% incidence in pancreatic ductal adenocarcinoma (PDAC), ∼12% in colorectal cancer (CRC) and ∼4% in non-small cell lung cancer (NSCLC). KRASG12D mutations disrupt the GTPase activity of the protein, resulting in elevated cellular levels of active, GTP-bound KRASG12D. KRASG12D mutations are therefore

Background: Patients with previously treated NSCLC have a high unmet medical need, with a median reported overall survival (OS) of <1 year. In NSCLC, KRAS G12D oncogenic mutations occur in approximately 4% of patients, but there are currently no RAS-targeted therapies approved for this population. Zoldonrasib (RMC-9805) is a potent, oral, RAS(ON) G12D-selective, covalent, tri-complex inhibitor targeting

Background: Neoadjuvant checkpoint blockade of locally advanced mismatch repair deficient (MMRd) rectal cancers results in a high rate of complete clinical responses that can eliminate the need for surgery. MMRd occurs broadly across solid tumors but is unknown if these findings could be extended in a tumor agnostic manner. Methods: Early stage MMRd solid tumors that were eligible for curative intent

Background: Breast cancer incidence is rising in women aged 20-49 years, yet data on trends in mortality for this age group are limited. Mortality varies by several factors, underscoring the need for comprehensive analyses. We, therefore, investigated trends in breast cancer incidence-based mortality (IBM) by race and molecular subtypes. Methods: We performed a population-based study of women aged

Colorectal Cancer (CRC) is the second leading cause of cancer-related deaths in the U.S. population, but minority groups experience significant disparities. Native Hawaiians (NH), who make up 0.4% of the U.S. population, face a higher mortality rate compared to Whites, with a rate of 52 per 100,000 in males (vs. 44 per 100,000) and 37 per 100,000 in females (vs. 34 per 100,000). This elevated CRC death

Background: Anti-CD40 agonistic antibodies have been explored in clinical trials over the last few decades; however, to date none have been approved. Systemic activation of CD40 by anti-CD40 antibodies can lead to adverse effects such as liver toxicity, infusion-related reactions, thrombocytopenia, and cytokine release syndrome, limiting the therapeutic window of these agents. Targeting CD40 activation

The RAS G12V mutation is among the most common oncogenic drivers in pancreatic, colorectal, and non-small cell lung cancers. Within a tumor cell, RAS G12V exists predominantly in the active, GTP-bound (“RAS(ON)”) state leading to excessive downstream oncogenic signaling. The intrinsic GTP hydrolysis rate of RAS G12V is about 12-fold lower than that of KRAS G12C, biasing the cellular RAS G12V pool to

Background: Neoadjuvant and adjuvant immune checkpoint inhibitors added to SOC (surgery + postoperative radiotherapy [PORT] ± concurrent chemotherapy) yielded promising efficacy results in participants (pts) with LA HNSCC in early phase studies. The randomized, open-label, phase 3 KEYNOTE-689 study (NCT03765918) evaluates neoadjuvant and adjuvant pembrolizumab + SOC vs SOC in this population. Methods:

KRAS is one of the most frequently mutated oncogenes in human cancer (present in ∼25% of cancers). Recent approvals of covalent KRAS G12C inhibitors (KRAS G12Ci) have demonstrated that this once “undruggable” target can now be inhibited with small-molecule allosteric inhibitors to deliver meaningful clinical benefit. Approved inhibitors (sotorasib & adagrasib) are only effective for tumors harboring

Introduction: Pediatric sarcomas are challenging to accurately classify due to their rarity and the wide diversity of subtypes. The process requires highly specialized pathologists as well as molecular and genetic testing that is expensive, takes time, and is not universally available. Deep neural network models (DNNs) trained on histopathology slides can reduce the time and cost to diagnosis and attenuate

Background: Patients with early-stage solid tumors who harbor minimal residual disease (MRD) following surgical resection as detected by circulating tumor DNA (ctDNA), have a high risk of recurrence. It remains uncertain whether therapeutic intervention of MRD in this context reduces cancer recurrence. We evaluated the efficacy of PD-1 blockade in resected early-stage mismatch repair deficient (MMRd)

Background: The ROME trial, a phase II multicenter study, enrolled 1,794 patients with advanced solid tumors. Centralized next-generation sequencing (NGS) was performed on both tissue and liquid biopsies using FoundationOne CDx and FoundationOne Liquid CDx. A centralized Molecular Tumor Board (MTB) reviewed results to identify actionable alterations, with 400 patients subsequently randomized to tailored

Regulatory T (Treg) cell abundance in the tumor microenvironment is associated with poor responses to immunotherapies, such as nivolumab. The transcription factors Helios (IKZF2) and Eos (IKZF4) are abundantly expressed in Treg cells and contribute to the immunosuppressive phenotype associated with this T-cell subset. We and others have postulated that degradation of Helios and Eos could re-polarize

In acute myeloid leukemia (AML), genetic mutations distort hematopoietic differentiation, resulting in the accumulation of leukemic blasts. However, it remains unclear how these mutations intersect with the cellular origins of each patient's disease, and whether distinct sets of mutations converge upon similar differentiation patterns. Single-cell RNA sequencing has enabled high-resolution mapping

NRAS is commonly mutated in several different types of human cancer. NRAS-mutant tumors are aggressive and associated with poor outcomes. Although the development of targeted therapies as well as immune checkpoint inhibitors has led to a substantial improvement in the overall survival of patients with NRAS wild-type tumors, current therapies for NRAS-mutant cancers are limited. Here, analysis of RNA-sequencing

Ferroptosis is a non-apoptotic form of cell death driven by iron-dependent lipid peroxide accumulation. Colorectal cancer (CRC) cells feature elevated intracellular iron and reactive oxygen species (ROS) that heighten ferroptosis sensitivity. The ferroptosis inducer (S)-RSL3 ([1S,3R]-RSL3) is widely described as a selective inhibitor of the selenocysteine-containing enzyme (selenoprotein) glutathione

Physical constraints like compression influence cancer cell invasion and transcriptional dynamics in various tumors. Liver cancer is characterized by the rapid proliferation of tumor cells within a densely packed tissue matrix, subjecting the cancer cells to crowding and compression. The highly dysregulated mechanical environment highlights the need to elucidate the broader impact of compression on

Intestinal metaplasia (IM) represents a precancerous condition associated with an increased gastric cancer (GC) risk. A better understanding of whether and how precancerous lesions progress to GC is crucial for patient stratification and personalized prevention. Here, we reconstruct evolutionary trajectories of genomic alterations in 330 multi-region matched samples of IM and tumors from 93 GC patients

Emerging spatial profiling technologies have revolutionized our understanding of how tissue architecture shapes disease progression, yet the contribution of cellular diversity remains underexplored. Here, Ding and colleagues introduce multiomics and ecological spatial analysis (MESA), an ecology-inspired framework that integrates spatial and single-cell expression data to quantify tissue diversity

Halting breast cancer metastatic relapse following primary tumor removal remains challenging due to a lack of specific vulnerabilities to target during the clinical dormancy phase. To identify such vulnerabilities, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). The dormancy-prone 4T07

Chromosomal 11q13.3 amplification is the most common gene copy-number variation event in head and neck squamous cell carcinoma (HNSCC) that corresponds with poor prognosis. Although cyclin D1, a G1/S phase cell-cycle regulatory protein at this locus, is considered as a key driver of malignant progression, further exploration is needed to develop more effective targets for cases with this amplification

Breast cancers with BRCA1 or BRCA2 mutations are defective in repair of DNA double-strand breaks by homologous recombination, resulting in compensatory error-prone repair that causes genomic instability. Poly(ADP-ribose) polymerase inhibitors (PARPi) are FDA-approved to treat homologous recombination–defective cancers, inducing therapy responses by synthetic lethality. PARPis increase micronuclei formation

Patient behavior and physiology can directly affect cancer metabolism. Smoking is the leading risk factor for non-small cell lung cancer (NSCLC). Here, we identified that smoking modulates lung cancer cell metabolism through altered protein post-translational modification. Proteomic analyses identified elevated K251 succinylation (K251-Su) of GAPDH, a key enzyme in glycolysis, in NSCLC samples, and

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive cancer affecting young women, driven by inactivating mutations in SMARCA4, a key SWI/SNF chromatin remodeling gene. To uncover its druggable vulnerabilities, we performed a compound screen and found that SCCOHT cells and tumors were sensitive to PARP inhibitors. Paradoxically, SCCOHT displayed BRCA-deficient traits

Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) limits the efficacy of molecular targeted therapy in non-small cell lung cancer (NSCLC). Metabolic reprogramming is a hallmark of lung cancer that could contribute to TKI resistance. Through systematic screening and verification, we identified a role for the long noncoding RNA (lncRNA) MYLK-AS1 supporting acquired TKI resistance in lung

Segmental duplications (SDs) are blocks of genomic DNA with high sequence homology that are hotspots for chromosomal rearrangements, coinciding with copy-number and single-nucleotide variations in the population. SDs could represent unstable genomic regions that are susceptible to somatic alterations in human cancers. Here, we aimed to elucidate the genomic locations of SDs in relation to cancer-related

Tobacco smoking and alcohol consumption are among the most significant, yet preventable, behavioral risk factors for cancer. In a recent paper in Nature Genetics, Torrens and colleagues performed whole-genome sequencing of 265 head and neck cancer (HNC) samples collected from eight countries across Europe and South America. They investigated the mechanisms underlying HNC development using mutational

The transcription factor PAX5 is a major target of genetic alterations in human B-cell precursor acute lymphoblastic leukemia (B-ALL). Among the alterations, the P80R mutation affecting the DNA-binding domain represents the most frequent PAX5 point mutation in B-ALL. In contrast to other somatic PAX5 mutations, PAX5P80R defines a distinct B-ALL subtype characterized by a unique transcriptional program

Therapeutic innate immune stimulation within the tumor microenvironment can potentiate endogenous antitumor T cell immunity. Strategies for controlled activation of cGAS/STING signaling are currently under intense investigation. DNase 3’-repair exonuclease 1 (TREX1) is essential for cellular DNA disposal, which prevents autoimmunity ensuing from cGAS/STING activation by endogenous DNA. TREX1-deficient

Combination therapies are one potential approach to improve the outcomes of patients with refractory or relapsed disease. However, comprehensive testing in scarce primary patient material is hampered by the many drug combination possibilities. Furthermore, inter- and intra-patient heterogeneity necessitates personalized treatment optimization approaches that effectively exploit patient-specific vulnerabilities

Breast and ovarian cancers harboring homologous recombination deficiency (HRD) are sensitive to PARP inhibitors and platinum chemotherapy. Conventionally, detecting HRD involves screening for defects in BRCA1, BRCA2, and other relevant genes. Recent analyses have shown that HRD cancers exhibit characteristic mutational signatures due to the activities of HRD-associated mutational processes. At least

Three-prime repair exonuclease 1 (TREX1) is the major DNase in mammalian cells that degrades cytosolic DNA to prevent activation of the cGAS-STING pathway. Genotoxic stress, DNA damage, and radiotherapy induce TREX1 expression in cancer cells, allowing them to evade innate immune activation of type I interferon (IFN-I)-mediated antitumor response. Therefore, targeting TREX1 could represent a potential

Triggering cancer cell death by inducing DNA damage is the primary aim of radiation therapy; however, normal cells are also damaged. Here, we showed that delivery of only four synthetic guide RNAs (sgRNAs) with Cas9 endonuclease efficiently induced simultaneous DNA double-strand breaks, resulting in efficient cell death in a cell type-specific manner. Off-target effects of Cas9 endonuclease were prevented

The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces PD-L1, leading to suppression of anti-tumor immunity. Here, we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. ISR coordinately induced CD155 and PD-L1

The tumor microenvironment plays a crucial role in shaping the tumor phenotype, yet replicating its complexity in vitro remains challenging. Traditional two-dimensional culture models lack physiologic relevance, and three-dimensional models often fail to fully capture native extracellular matrix (ECM) composition and cellular heterogeneity. In this issue of Cancer Research, Buckenmeyer and colleagues

Breast cancer (BC) is a heterogeneous disease with diverse morphological and molecular subtypes. Preclinical models that recapitulate the heterogeneity of human BC are needed to advance our fundamental understanding of what makes BC an aggressive disease. To study mechanisms underlying BC progression, we generated orthotopic cell line-derived xenograft (CDX) models from 20 different human BC cell lines

Both acquired mutations and germline genetic variation are known risk factors for chronic lymphocytic leukemia (CLL). Joint characterization of germline, acquired, and clinical risk has the potential to improve CLL risk prediction. Here, we investigated whether inclusion of a CLL-associated polygenic score (PGS) and two common types of clonal hematopoiesis (CH), autosomal mosaic chromosomal alterations

Despite the remarkable success of CAR T cells in certain hematological malignancies, only modest responses have been achieved in solid tumors. Defective cell death pathways have recently been suggested as a tumor-intrinsic form of resistance to CAR T cell treatment. Here, we showed that insufficient activity of the innate RNA-sensing receptor system, RIG I/MAVS, leads to tumor cell-inherent resistance

Accurate preoperative assessment of lymph node metastasis (LNM) and overall survival (OS) status is essential for patients with locally advanced gastric cancer (LAGC) receiving neoadjuvant chemotherapy (NAC), providing timely guidance for clinical decision-making. However, current approaches to evaluate LNM and OS have limited accuracy. In this study, we used longitudinal CT images from 1,021 LAGC

Trastuzumab deruxtecan (T-DXd) is a transformative HER2-targeting antibody–drug conjugate (ADC) for treating breast cancer. Unfortunately, T-DXd has also been implicated in causing fatal interstitial lung disease (ILD) in multiple clinical trials. A better understanding of the mechanistic basis of these ADC-induced adverse effects could enable development of strategies to prevent or treat T-DXd–related