Abstract Genetically engineered allogeneic regulatory T cells (Tregs) represent a promising off-the-shelf therapy to prevent graft-versus-host disease and transplant rejection, but their clinical utility is constrained by immune rejection and alloreactivity. Using CRISPR-Cas editing, we generated hypoimmunogenic human Tregs through multiplex knockout of B2M (reducing HLA class I), TCRα/β (eliminating receptor-mediated alloreactivity), and SRC-3 (a transcriptional coactivator linked to Treg stability). In prior murine studies, SRC-3 disruption enhanced tumor clearance, but in human Tregs, its deletion impaired suppressive function, underscoring SRC-3’s role in maintaining lineage identity. Functionally, SRC-3 knockout Tregs failed to suppress effector T cell proliferation, a defect mirrored in triple knockout (TCR+B2M+SRC-3) cells. Co-culture with unedited Tregs restored suppression, suggesting functional compensation. FOXP3 protein levels were markedly reduced in SRC-3 and triple knockout Tregs, consistent with destabilized lineage commitment. These findings highlight SRC-3, TCR, and B2M as central regulators of transcriptional and antigen-presentation pathways shaping Treg identity. RNA sequencing revealed that triple knockout Tregs exhibited increased transcript diversity compared to controls. SRC-1/NCOA1 and SRC-2/NCOA2 were upregulated in SRC-3 and triple knockout samples, while B2M and TRAC were strongly downregulated in triple knockouts. Chemokine transcripts were elevated in SRC-3 and triple knockout Tregs, with triple knockouts also showing diverse cytokine upregulation. Collectively, these results demonstrate that while genome editing can enhance allogeneic compatibility, SRC-3 is indispensable for human Treg stability and suppressive function. Effective engineering of universal Tregs must therefore balance hypoimmunogenic design with preservation of functional integrity for adoptive cell therapy. Citation Format: Subhashree Pradhan, Bryan Nikolai, Aiden Lynn Moser, Davis Alexander Graham, Lanz Rainer, Bert W O'Malley, David Lonard. CRISPR-Cas engineering of allogeneic regulatory T cells reveals an essential role for steroid receptor coactivator 3 (SRC-3) in maintaining FOXP3 expression and suppressive function [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 5960.

Abstract While Steroid Receptor Coactivator 3 (SRC-3) is best known for its role in promoting proliferation of breast cancer cells, our group has recently identified a key role for SRC-3 in regulatory T cells (Tregs). Treg specific knockout (KO) of SRC-3 results in the long-term eradication of primary tumors in a syngeneic model of triple negative breast cancer. SRC-3 KO Treg mice also can resist rechallenge with a second dose of tumor cells. This long-term anti-tumor immunity points to the potential that SRC-3 KO Treg cells are differentiating into T memory cells. Our data shows that SRC-3 KO Tregs express higher levels of the T memory cell markers CD44 and CD62L than wild type Tregs and that SRC-3 KO Tregs downregulate inducible T-cell co-stimulator (ICOS), c-MAF, and interleukin 10 (IL-10). Utilizing single cell multiome sequencing and subsequent functional assays, we aim to further delineate the role of SRC-3 in Tregs and the impact of SRC-3 KO Tregs on the broader effector immune system. Through these assays we will gain insight into the role that SRC-3 has on T memory cell formation and function and the impact of SRC-3 KO Tregs on other immune cells. This work aims to provide a mechanistic delineation of the long term anti-tumor effects of SRC-3 KO Tregs. Citation Format: Davis A. Graham, Yan Xia, Subhashree Pradhan, Amrit Koirala, Xiaobin Yu, Adam M. Dean, Bryan C. Nikolai, Aiden L. Moser, Jianming Xu, Cristian Coarfa, Bert W. O'Malley, David M. Lonard. Role of SRC-3 in regulatory T cells as a modulator of activation and immunological memory [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 165.

Abstract Introduction: Regulatory T cells (Tregs) play a critical role in balancing immune responses to prevent autoimmune disease through their immunosuppressive activities. However, the suppressive activity of Tregs can be coopted by cancers to evade immune surveillance, leading to tumor progression. Steroid receptor coactivator 3 (SRC-3) is highly expressed in Tregs and we have discovered that genentically engineered mice with SRC-3 specifically knocked out in Tregs are resistant to breast cancer growth, suggesting SRC-3-KO Tregs are a potential therapy for breast cancer patients. In this study, we explored the therapeutic effect of SRC-3 KO Tregs in a mouse model of triple negative breast cancer (TNBC). Method: A mouse syngeneic, immune-intact breast cancer model was produced by injecting luciferase expressing E0771 TNBC cells into the fourth mammary pad. To closely mimic a clinical scenario, Treg cells were isolated from the spleens of tumor-bearing C57BL/6J donor mice. After disrupting the SRC-3 gene by CRISPR/Cas9 targeting, Tregs were allowed to recover and proliferate in vitro for 4 days before collecting them for adoptive cell therapy (ACT) into C57BL/6J recipient mice with established breast cancer. Wild type Treg cells without gene editing were used as control. Tumor growth was monitored by bioluminescence imaging twice a week for 3 weeks. By the end of experiment, mice were sacrificed and spleen, blood, and tumors were collected for flow cytometry analysis as well as immunofluorescence staining. Results: ACT of SRC-3 KO Tregs significantly reduced tumor growth or cleared tumosr in all treated mice. SRC-3KO Treg treatment also prolonged mice overall survival. Both ACTed WT and SRC-3KO Tregs were detected in the spleen, blood, and tumors of recipient mice. Moreover, many more cytotoxic T cells, including CD8 and granzyme B+ cells were found in SRC-3-KO Treg treated tumor-bearing mice, compared to WT Treg treated controls. Conclusion: Deleting the SRC-3 gene in Tregs derived from tumor-bearing donors possess potent anti-tumor effects in an immune-intact mouse breast cancer model. These SRC-3 KO Tregs exert their effects by enhancing the cytotoxicity of effector CD8+ T cells in the tumor microenvironment. Our results reinforce the clinical potential of using SRC-3 KO Treg cells as an effective immunotherapy for TNBCs. Citation Format: Yan Xia, Yosef Gilad, Davis Graham, Bert W. O'Malley, David M. Lonard. Preclinic study of src3-ko regulatory T cells in mouse breast cancer model [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 167.

This phase II trial of transoral surgery (TOS) with deintensified postoperative management in human papillomavirus (HPV)-associated oropharynx cancer (OPC) enrolled patients with resectable cT1-2 stage III/IV American Joint Committee on Cancer (AJCC) seventh edition p16+ OPC without matted neck nodes. Those with clear margins, 0-1 + nodes (LN), and no extranodal extension (ENE) were observed (arm A); those with clear margins, 2-4 + LN, or ENE ≤1 mm were randomly assigned to 50 Gy (arm B) or 60 Gy (arm C); and those with involved margins, >4 + LN, or >1 mm ENE received weekly cisplatin and 60-66 Gy (arm D). Among 359 evaluable patients, the 54-month progression-free (PFS) and overall survival (OS) were 90.6% (90% CI, 87.2% to 93.1%) and 95.3% (93.0% to 96.9%), respectively. The 54-month PFS by arm was A 93.2% (79.6% to 97.8%; all four recurrences among N1 patients), B 94.9% (89.7% to 97.5%), C 90.2% (82.7% to 94.6%), and D 85.5% (77.5% to 90.8%). The 54-month OS by arm was A 97.1% (85.7% to 99.4%), B 97.9% (93.5% to 99.3%), C 95.1% (90.1% to 97.6%), and D 92.5% (86.9% to 95.7%). PFS or OS did not differ by primary site or smoking history. TOS and neck dissection with deintensified postoperative management results in outstanding 54-month PFS and OS. Among patients with favorable pathologic characteristics, those with N1 disease are at risk of late recurrence without radiation.

Defective placentation is a recognized etiology for several gestational complications that include early pregnancy loss, preeclampsia, and intrauterine growth restriction. Sustained viability, migration, and invasion are essential cellular properties for embryonic extravillous trophoblasts to execute their roles in placental development and function, while derailment of these cellular processes is linked to placental disorders. Although the cellular functions of extravillous trophoblasts are well recognized, our understanding of the pivotal molecular determinants of these functions is incomplete. Using the HTR-8/SVneo immortalized human extravillous trophoblast cell line, we report that steroid receptor coactivator-2 (SRC-2), a coregulator of transcription factor-mediated gene expression, is essential for extravillous trophoblast cell viability, motility, and invasion. Genome-scale transcriptomics identified an SRC-2-dependent transcriptome in HTR-8/SVneo cells that encodes a diverse spectrum of proteins involved in placental tissue development and function. Underscoring the utility of this transcriptomic dataset, we demonstrate that WNT family member 9A (WNT 9A) is not only regulated by SRC-2 but is also crucial for maintaining many of the above SRC-2-dependent cellular functions of human extravillous trophoblasts.

Objectives (1) To determine the incidence of occult contralateral cervical lymph node metastasis in patients with early-stage HPV-associated base-of-tongue (BOT) oropharyngeal squamous cell carcinoma (OPSCC) treated with primary surgery; and (2) to compare survival and recurrence in patients who did and did not undergo contralateral neck treatment.Background Contralateral neck management in patients with early-stage HPV+ OPSCC of the BOT treated surgically remains controversial. Despite lacking data, most patients receive surgery and/or radiation to the contralateral neck based on historical incidence of occult lymph node metastasis in OPSCC.Methods A retrospective chart review of patients with AJCC 7th edition pT1-2, pN0-1 HPV+ BOT OPSCC undergoing transoral robotic BOT resection and ipsilateral neck dissection with adjuvant treatment was conducted. The incidence of occult contralateral nodal metastasis was assessed. Overall and disease-free survival were compared between patients who did and did not undergo contralateral neck treatment.Results Of 106 patients meeting inclusion criteria, 46 (43.3%) did not undergo treatment of the contralateral neck with radiation or lymphadenectomy, whereas 29 (27.4%) received radiation alone to the contralateral neck, and 31 (29.2%) underwent elective contralateral neck dissection without identification of occult metastasis in any case. Overall survival (HR: 0.95, 95% CI: 0.23-4.00) and disease-free survival (HR: 1.43, CI: 0.55-3.71) did not significantly differ between patients who did and did not receive treatment to the contralateral neck.Conclusion Risk of occult contralateral cervical lymph node metastasis in patients with early-stage HPV-associated BOT OPSCC treated with primary surgery was low, prompting consideration of forgoing contralateral neck treatment in these patients.

Regulatory T cells (Tregs) play a crucial role in the immune system, and their dysfunction can lead to the development of autoimmune conditions. In cancer, tumors frequently hijack the immunosuppressive function of Tregs to evade immune responses. Due to their central role in key pathological processes, Tregs have gained increasing attention as promising targets for various clinical applications. However, their relative scarcity (∼5% to 10% of CD4+ T cells) and instability presents a technical challenge for research and therapeutic development. In congenic animal models used to investigate autologous cell transfer–based therapies, this challenge is even greater, as Treg donor animals may only be able to provide cells to a small number of recipient mice. Here, we present an optimized protocol for ex vivo editing and expansion of mouse Tregs. Because a recent study demonstrated the anticancer potential of SRC-3 KO mouse Tregs, we use them here as a case study.

We recently discovered that steroid receptor coactivators (SRCs) SRCs-1, 2 and 3, are abundantly expressed in cardiac fibroblasts (CFs) and their activation with the SRC small molecule stimulator MCB-613 improves cardiac function and dramatically lowers pro-fibrotic signaling in CFs post-myocardial infarction. These findings suggest that CF-derived SRC activation could be beneficial in the mitigation of chronic heart failure after ischemic insult. However, the cardioprotective mechanisms by which CFs contribute to cardiac pathological remodeling are unclear. Here we present studies designed to identify the molecular and cellular circuitry that governs the anti-fibrotic effects of an MCB-613 derivative, MCB-613-10-1, in CFs. We performed cytokine profiling and whole transcriptome and proteome analyses of CF-derived signals in response to MCB-613-10-1. We identified the NRF2 pathway as a direct MCB-613-10-1 therapeutic target for promoting resistance to oxidative stress in CFs. We show that MCB-613-10-1 promotes cell survival of anti-fibrotic CFs exposed to oxidative stress by suppressing apoptosis. We demonstrate that an increase in HMOX1 expression contributes to CF resistance to oxidative stress-mediated apoptosis via a mechanism involving SRC co-activation of NRF2, hence reducing inflammation and fibrosis. We provide evidence that MCB-613-10-1 acts as a protectant against oxidative stress-induced mitochondrial damage. Our data reveal that SRC stimulation of the NRF2 transcriptional network promotes resistance to oxidative stress and highlights a mechanistic approach toward addressing pathologic cardiac remodeling.

Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor’s transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback mechanism to regulate P4-responsive genes. Conversely, in endometrial pathology (endometriosis), E2-induced GREB1 modulates E2-dependent gene expression to promote the growth of endometriotic lesions in mice. This differential action of GREB1 exerted by a common feed-forward mechanism with steroid receptors advances our understanding of mechanisms that underlie cell- and tissue-specific steroid hormone actions.

6009 Background: E3311 is a phase II trial of TOS by credentialed surgeons with pathology-driven deintensified post-operative management in HPV+ OPC. Intermediate risk patients were randomized between standard and reduced dose radiation. We present mature outcome data, at median follow up of 52.4 months (m). Methods: Patients were eligible who had resectable cT1-2 stage III/IV AJCC7 p16+ OPC without matted neck nodes. Those with clear margins, 0-1 + nodes (LN), and no extranodal extension (ENE) were observed (Arm A, N=38); those with clear margins, 2-4 + LN, or ENE ≤1mm were randomized to 50Gy (Arm B, N=100) or 60Gy (Arm C, N=108); those with involved margins, >4 + LN, or >1mm ENE received weekly cisplatin 40 mg/m2 and 60-66Gy (Arm D, N=113). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared using a log-rank test, stratified by arm for comparisons of primary site and smoking history. Results: Among 359 evaluable patients, 54-m PFS and OS were 90.6% (90% CI: 87.2%, 93.1%) and 95.3% (90% CI: 93.0%, 96.9%). 54-m PFS by arm was: A 93.2% (90% CI: 79.6%, 97.8%); B 94.9% (90% CI: 89.7%, 97.5%); C 90.2% (90% CI: 82.7%, 94.6%) and D 85.5% (90% CI: 77.5%, 90.8%). 54-m OS by arm was: A 97.1% (90% CI: 85.7%, 99.4%); B 97.9% (90% CI: 93.5%, 99.3%), C 95.1% (90% CI: 90.1%, 97.6%) and D 92.5% (90% CI: 86.9%, 95.7%). Among patients in Arm A, 11 had N0 and 27 N1 stage. Median Arm A lymph node yield (LNY) was 29 (11 to 91 LN) and did not differ for patients with/without recurrence (p=0.83). All Arm A recurrences were in N1 patients: 1 at 18 m and 3 at > 40 m. No significant difference in PFS or OS was observed by prescribed radiation dose for intermediate risk patients (Arm B vs. C). Outcome did not differ by primary site of tonsil vs. other OPC (oOPC): 54-m PFS Tonsil 89.3% (90% CI: 84.9%, 92.5%) vs. oOPC 92.9% (90% CI: 87.0%, 96.2%), p=0.28, and 54-m OS Tonsil 94.6% (90% CI: 91.5%, 96.6%) vs oOPC 96.6% (90% CI: 92.4%, 98.5%), p=0.35. Smoking history also did not impact outcome. 54-m PFS was 89.9% (90% CI: 85.9%, 92.9%) for those with ≤10 pack-years (PY) tobacco exposure and 91.7% (90% CI: 83.9%, 95.9%) for those with >10 PY. Conclusions: TOS, neck dissection with deintensified risk-based post-operative management results in outstanding 54-m PFS and OS across all subsites of T1-2 p16+ OPC, irrespective of smoking history. Late recurrence is not increased when post-operative radiation is reduced from 60 to 50Gy for intermediate risk patients. Pathologic >1mm ENE (N=87), involved margin (N=12) or >4 involved LN (N=30) accurately identify patients at increased recurrence risk and outcomes were favorable among such patients. Among patients with favorable pathologic characteristics, a subset with N1 disease are at risk for late recurrence and further characterization of these patients is warranted. Clinical trial information: NCT01898494 .

Steroid receptor coactivators (SRCs) are a family of nuclear receptor (NR) coregulators comprised of three evolutionarily related, yet distinct proteins SRC-1, SRC-2 and SRC-3. The SRCs interact with NRs and other transcription factors to regulate their transcriptional activity, impacting a wide variety of physiological and pathological processes. Abnormal expression or dysfunction of SRCs is associated with a diverse range of pathological conditions, including metabolic disorders, genetic and reproductive malfunctioning, impaired embryogenesis and most notably cancer which is the focus of this review. As key integrators of NR and growth factor signaling pathways, SRCs regulate multiple oncogenic programs, particularly in hormone-related malignancies, and thus represent attractive biological targets for cancer treatment. Here we review the evolution of the discovery process for small molecule targeting agents of SRCs and the opportunities they present for cancer therapy.

Chemotherapy is often combined with immune checkpoint inhibitor (ICIs) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers, many immunologically cold tumors remain unresponsive. The mechanisms determining the immunogenicity of chemotherapy are elusive. Here, we identify the ER stress sensor IRE1a as a critical checkpoint that restricts the immunostimulatory effects of taxane chemotherapy and prevents the innate immune recognition of immunologically cold triple-negative breast cancer (TNBC). IRE1a RNase silences taxane-induced double-stranded RNA (dsRNA) through regulated IRE1-dependent decay (RIDD) to prevent NLRP3 inflammasome-dependent pyroptosis. Inhibition of IRE1a in Trp53-/- TNBC allows taxane to induce extensive dsRNAs that are sensed by ZBP1, which in turn activates NLRP3-GSDMD-mediated pyroptosis. Consequently, IRE1a RNase inhibitor plus taxane converts PD-L1-negative, ICI-unresponsive TNBC tumors into PD-L1high immunogenic tumors that are hyper-sensitive to ICI. We reveal IRE1a as a cancer cell defense mechanism that prevents taxane-induced danger signal accumulation and pyroptotic cell death.

Steroid receptor coactivators (SRCs) are master regulators of transcription that play key roles in human physiology and pathology. SRCs are particularly important for the regulation of the immune system with major roles in lymphocyte fate determination and function, macrophage activity, regulation of nuclear factor κB (NF-κB) transcriptional activity and other immune system biology. The three members of the p160 SRC family comprise a network of immune-regulatory proteins that can function independently or act in synergy with each other, and compensate for - or moderate - the activity of other SRCs. Recent evidence indicates that the SRCs are key participants in governing numerous aspects of CD4+ T cell biology. Here we review findings that establish the SRCs as essential regulators of regulatory T cells (Tregs) and T helper 17 (Th17) cells, with a focus on their crucial roles in Treg immunity in cancer and Treg-Th17 cell phenotypic plasticity.

INTRODUCTION: Stroke is the leading cause of adult disability and the fifth leading cause of mortality in the United States. Despite the study of many neuroprotective agents for acute ischemic stroke, none has been shown to be effective in large randomized clinical trials. Steroid receptor coactivator (SRC) is a promising class of agents since they are involved in cellular proliferation and regeneration, immune modulation, angiogenesis, antioxidant protection and are expressed in the brain. METHODS: Twenty c57bl/6 mice were randomly assigned to control or treatment groups (n = 10 mice per group). All mice underwent middle cerebral artery occlusion for 90 minutes followed by reperfusion via the intraluminal filament method. Occlusion was confirmed by laser doppler flowmetry. Intraperitoneal injections of saline (control) or 10-1 (treatment) were given 30 minutes after reperfusion. Each animal was tested using a modified Bederson’s neurological deficit scale (mNDS) and euthanized at the conclusion of the 24-hour survival period. Brain slices were stained with 2,3,5- triphenyltetrazolium chloride (TTC) to identify ischemic brain tissue. RESULTS: When compared with the control group, 10-1 treated mice showed significantly lower mNDS scores (p = 0.000336) and incidence of circling (p = 0.00256). Calculated infarct volumes, based on TTC staining, of the 10-1 treated group were significantly lower (p = 0.0009) when compared to the control group. CONCLUSIONS: We have shown that 10-1 is a promising therapeutic agent and provides substantial neuroprotection through its many multicellular processes in a rodent study. Current studies are being conducted to investigate the mechanism of 10-1 as neuroprotectant.

Steroid receptor coactivator 3 (SRC-3) is a critical mediator of many intracellular signaling pathways that are crucial for cancer proliferation and metastasis. In this study, we performed structure-activity relationship exploration and drug-like optimization of the hit compound SI-2, guided by in vitro/in vivo metabolism studies and cytotoxicity assays. Our efforts led to the discovery of two lead compounds, SI-10 and SI-12. Both compounds exhibit potent cytotoxicity against a panel of human cancer cell lines and demonstrate acceptable pharmacokinetic properties. A biotinylated estrogen response element pull-down assay demonstrated that SI-12 could disrupt the recruitment of SRC-3 and p300 in the estrogen receptor complex. Importantly, SI-10 and SI-12 significantly inhibited tumor growth and metastasis in vivo without appreciable acute toxicity. These results demonstrate the potential of SI-10 and SI-12 as drug candidates for cancer therapy, given their potent SRC-3 inhibition and promising pharmacokinetic and toxicity profiles.

The purpose of this study was to evaluate the feasibility and safety of dose-escalated proton beam therapy for treating chordomas and chondrosarcomas of the skull base and spine. A prospective cohort of 54 patients (42 with chordomas and 12 with chondrosarcomas) was enrolled between 2010 and 2018. The primary endpoints were feasibility and <20% rate of acute grade ≥3 toxicity, while secondary endpoints included cancer-specific outcomes and toxicities. Patients were followed with MRI or CT at three-month intervals. Proton beam therapy was delivered with doses up to 79.2 Gy using protons only, combination protons/IMRT, or IMRT only. Feasibility endpoints were met, with only 2 out of 54 patient RT plans failing to meet dosimetric constraints with protons and 4 out of 54 experiencing a delay or treatment break >5 days, none for toxicities related to treatment. There were no grade 4 acute toxicities, and one grade 3 acute toxicity (sensory neuropathy). The only two grade 3 late toxicities recorded, osteoradionecrosis and intranasal carotid blowout (mild and not emergently treated), occurred in a single patient. We report overall survival as 83% at 5 years, with local failure-free survival and progression-free survival rates of 72% and 68%, respectively. Five patients developed distant disease, and among the 9/54 patients who died, 4 deaths were not attributed to treatment or recurrence. Our findings suggest that high-dose proton therapy alone or in combination with IMRT is a safe and effective treatment option for chordomas and chondrosarcomas of the skull base and spine.

Despite substantial advances in targeting mutant KRAS, tumor resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report proteostasis reprogramming as a key convergence point of multiple KRASi-resistance mechanisms. Inactivation of oncogenic KRAS down-regulated both the heat shock response and the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1α was selectively reactivated in an ER stress–independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1α protein stability through extracellular signal–regulated kinase (ERK)–dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In KRASi-resistant tumors, both reactivated ERK and hyperactivated AKT restored IRE1α phosphorylation and stability. Suppression of IRE1α overcame resistance to KRASi. This study reveals a druggable mechanism that leads to proteostasis reprogramming and facilitates KRASi resistance.

Objectives: To determine whether 2 different methods of post-operative head and neck free flap monitoring affect flap failure and complication rates. Methods: A retrospective chart review of 803 free flaps performed for head and neck reconstruction by the same microvascular surgeon between July 2013 and July 2020 at 2 separate hospitals within the same healthcare system. Four-hundred ten free flaps (51%) were performed at Hospital A, a medical center where flap checks were performed at frequent, scheduled intervals by in-house resident physicians and nurses; 393 free flaps (49%) were performed at Hospital B, a medical center where flap checks were performed regularly by nursing staff with resident physician evaluation as needed. Total free flap failure, partial free flap failure, and complications (consisting of wound infection, fistula, and reoperation within 1 month) were assessed. Results: There were no significant differences between Hospitals A and B when comparing rates of total free flap failure, partial free flap failure, complication, or re-operation ( P = .27, P = .66, P = .65, P = .29, respectively). There were no significant differences in urgent re-operation rates for flap compromise secondary to thrombosis and hematoma ( P = .54). Conclusions: In our series, free flap outcomes did not vary based on the degree of flap monitoring by resident physicians. This data supports the ability of a high-volume, well-trained, nursing-led flap monitoring program to detect flap compromise in an efficient fashion while limiting resident physician obligations in the age of resident duty hour restrictions.