One and five-year efficacy of tension-free vaginal tape (TVT) abbrevo and TVT-obturator in the treatment of stress urinary incontinence: a retrospective study.

BACKGROUND: Surgical interventions are more effective than nonsurgical approaches in providing a cure for stress urinary incontinence (SUI). In this study, we aimed to assess the benefits of tension-free vaginal tape (TVT) abbrevo by comparing its efficacy and complications to those of TVT obturator. METHODS AND RESULTS: 49 and 47 patients at The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University between January 2013 and December 2016 were included in the TVT-O and TVT-A groups, respectively. We evaluate the success rate and perioperative complications associated with TVT-O and TVT-A. A questionnaire that utilized the Patient Global Impression of Improvement (PGI-I) Scale was employed to assess the impact of surgery. Patients were followed up at 1 year, and 5 years after surgery. There were no statistically significant differences found in the efficacy of the TVT-A group and TVT-O group during both the one-year (p = 0.4) and five-year (p = 0.32) follow-up periods. In the period of one-year follow-up, 95.9% (n = 47) of patients in the TVT-O group and 95.8% (n = 45) of patients in the TVT-A group demonstrated improvement. During the period of five-year follow-up, 87.8% (n = 43) of patients in the TVT-O group and 93.6% (n = 44) of patients in the TVT-A group demonstrated improvement. CONCLUSIONS: Based on our findings, TVT-A and TVT-O procedures exhibited similarly high success rates and low frequencies of complications.

PUMA/RIP3 Mediates Chemotherapy Response via Necroptosis and Local Immune Activation in Colorectal Cancer.

Induction of programmed cell death (PCD) is a key cytotoxic effect of anticancer therapies. PCD is not confined to caspase-dependent apoptosis, but includes necroptosis, a regulated form of necrotic cell death controlled by receptor-interacting protein (RIP) kinases 1 and 3, and mixed lineage kinase domain-like (MLKL) pseudokinase. Necroptosis functions as a defense mechanism against oncogenic mutations and pathogens and can be induced by a variety of anticancer agents. However, the functional role and regulatory mechanisms of necroptosis in anticancer therapy are poorly understood. In this study, we found that RIP3-dependent but RIP1-independent necroptosis is engaged by 5-fluorouracil (5-FU) and other widely used antimetabolite drugs, and functions as a major mode of cell death in a subset of colorectal cancer cells that express RIP3. We identified a novel 5-FU-induced necroptosis pathway involving p53-mediated induction of the BH3-only Bcl-2 family protein, p53 upregulated modulator of apoptosis (PUMA), which promotes cytosolic release of mitochondrial DNA and stimulates its sensor z-DNA-binding protein 1 (ZBP1) to activate RIP3. PUMA/RIP3-dependent necroptosis mediates the in vitro and in vivo antitumor effects of 5-FU and promotes a robust antitumor immune response. Our findings provide a rationale for stimulating necroptosis to enhance tumor cell killing and antitumor immune response leading to improved colorectal cancer treatments.

Prostaglandin F2α synthase promotes oxaliplatin resistance in colorectal cancer through prostaglandin F2α-dependent and F2α-independent mechanism.

BACKGROUND: Oxaliplatin (Oxa) is the first-line chemotherapy drug for colorectal cancer (CRC), and Oxa resistance is crucial for treatment failure. Prostaglandin F2α synthase (PGF2α) (PGFS), an enzyme that catalyzes the production of PGF2α, is involved in the proliferation and growth of a variety of tumors. However, the role of PGFS in Oxa resistance in CRC remains unclear. AIM: To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC. METHODS: The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels. Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance (HCT116-OxR and HCT8-OxR) and their parental cell lines (HCT116 and HCT8) to assess its influence on cell proliferation, chemoresistance, apoptosis, and DNA damage. For determination of the underlying mechanisms, CRC cells were examined for platinum-DNA adducts and reactive oxygen species (ROS) levels in the presence of a PGFS inhibitor or its products. RESULTS: Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues. Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dose-dependent manner. Furthermore, overexpression of PGFS in parental CRC cells significantly attenuated Oxa-induced proliferative suppression, apoptosis, and DNA damage. In contrast, knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells (HCT116-OxR and HCT8-OxR) accentuated the effect of Oxa treatment in vitro and in vivo. The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa. Treatment with the PGFS-catalyzed product PGF2α reversed the effect of PGFS knockdown on Oxa sensitivity. Interestingly, PGFS inhibited the formation of platinum-DNA adducts in a PGF2α-independent manner. PGF2α exerts its protective effect against DNA damage by reducing ROS levels. CONCLUSION: PGFS promotes resistance to Oxa in CRC via both PGF2α-dependent and PGF2α-independent mechanisms.

Establishment of risk prediction model of postoperative pancreatic fistula after pancreatoduodenectomy: 2016 edition of definition and grading system of pancreatic fistula: a single center experience with 223 cases.

OBJECTIVE: To establish a risk prediction model for pancreatic fistula according to the pancreatic fistula standards of the 2016 edition. METHODS: Clinical data from 223 patients with PD admitted to Tianjin Third Central Hospital from January 2016 to December 2020 were retrospectively analyzed. Patients were divided into modeling (January 2016 to December 2018) and validation (January 2019 to December 2020) sets according to the time of admission. The risk factors for postoperative pancreatic fistula (POPF) were screened by univariate and multivariate logistic regression analyses, and a risk prediction model for POPF was established in the modeling set. This score was tested in the validation set. RESULTS: Logistic regression analysis showed that the main pancreatic duct index and CT value were independent risk factors according to the 2016 pancreatic fistula grading standard, based on which a risk prediction model for POPF was established. Receiver operating characteristic curve analysis showed that the area under the curve was 0.775 in the modeling set and 0.848 in the validation set. CONCLUSION: The main pancreatic duct index and CT value of the pancreas are closely related to the occurrence of pancreatic fistula after PD, and the established risk prediction model for pancreatic fistula has good prediction accuracy.

Y-box binding protein 1 augments sorafenib resistance via the PI3K/Akt signaling pathway in hepatocellular carcinoma.

BACKGROUND: Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown. AIM: To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC. METHODS: The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq). RESULTS: YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance. CONCLUSION: Overall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.

[The Value of CD44+ Mononuclear Cells and Spleen Stiffness Measurement in Minimal Residual Disease in Acute Myeloid Leukemia and Its Prognosis].

OBJECTIVE: To investigate the value of CD44+ mononuclear cells (MNC) and spleen stiffness measurement (SSM) in minimal residual disease (MRD) in acute myeloid leukemia (AML) and its prognosis. METHODS: Flow cytometry was used to detected the proportion of CD44+ and CD24+ MNC in 44 AML patients after induction chemotherapy. The SSM was tested by FS. The value of MNC and SSM in MRD and its prognosis was explored. RESULTS: The percentage of CD44+ MNC and SSM in MRD positive group were significantly higher than those in MRD negative group (P<0.05). In MRD positive group, there were positive correlation between CD44+ MNC, SSM and MRD level (r=0.998, r=0.939, P<0.05). The median EFS and OS in HCD44+ MNC and HSSM groups were significantly shorter than those in LCD44+ MNC and LSSM (P<0.05). CD24+ MNC showed no association with MRD and its prognosis. CONCLUSION: HCD44+ MNC and HSSM may be used to predict high level MRD and poor prognosis.

[Relationship between Leukocytes Derived Microparticles and Minimal Residual Disease and Prognosis of Acute Myeloid Leukemia].

OBJECTIVE: To detect the relationship between leukocytes derived microparticle (CD45+ MP) and minimal residual disease (MRD) and prognosis of acute myeloid leukemia (AML). METHODS: The expression of CD45+ MP, CD44+ MP and CD24+ MP in peripheral blood of 47 AML patients at the time after induction chemotherapy were detected by using flow cytometry, and the relationship between MP, MRD and prognosis were analyzed. RESULTS: The percentages of CD45+ MP, CD44+ MP and CD24+ MP in MRD positive group were significantly higher than those in MRD negative group. In MRD positive group, there were positive correlation between CD45+ MP, CD44+ MP, CD24+ MP and MRD level. The AUC of CD45+ MP, CD44+ MP, CD24+ MP in predicting positive MRD was 0.949, 0.782, and 0.817, respectively. The EFS and OS in HCD45+ MP, HCD44+ MP and HCD24+ MP groups were significantly shorter than low level group. CONCLUSION: High level of CD45+ MP, CD44+ MP, CD24+ MP can be used to predict high level MRD and poor prognosis.

Non-steroidal anti-inflammatory drugs induce immunogenic cell death in suppressing colorectal tumorigenesis.

Use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal cancer (CRC). However, the mechanism by which NSAIDs suppress colorectal tumorigenesis remains unclear. We previously showed that NSAIDs selectively kill emerging tumor cells via death receptor (DR) signaling and a synthetic lethal interaction mediated by the proapoptotic Bcl-2 family protein BID. In this study, we found NSAIDs induce endoplasmic reticulum (ER) stress to activate DR signaling and BID in tumor suppression. Importantly, our results unveiled an ER stress- and BID-dependent immunogenic effect of NSAIDs, which may be critical for tumor suppression. NSAID treatment induced hallmarks of immunogenic cell death (ICD) in CRC cells and colonic epithelial cells upon loss of APC tumor suppressor, and elevated tumor-infiltrating lymphocytes (TILs) in the polyps of APCMin/+ mice. ER stress inhibition or BID deletion abrogated the antitumor and immunogenic effects of NSAIDs. Furthermore, increased ER stress and TILs were detected in human advanced adenomas from NSAID-treated patients. Together, our results suggest that NSAIDs induce ER stress- and BID-mediated ICD to restore immunosurveillance and suppress colorectal tumor formation.

Direct Tumor Killing and Immunotherapy through Anti-SerpinB9 Therapy.

Cancer therapies kill tumors either directly or indirectly by evoking immune responses and have been combined with varying levels of success. Here, we describe a paradigm to control cancer growth that is based on both direct tumor killing and the triggering of protective immunity. Genetic ablation of serine protease inhibitor SerpinB9 (Sb9) results in the death of tumor cells in a granzyme B (GrB)-dependent manner. Sb9-deficient mice exhibited protective T cell-based host immunity to tumors in association with a decline in GrB-expressing immunosuppressive cells within the tumor microenvironment (TME). Maximal protection against tumor development was observed when the tumor and host were deficient in Sb9. The therapeutic utility of Sb9 inhibition was demonstrated by the control of tumor growth, resulting in increased survival times in mice. Our studies describe a molecular target that permits a combination of tumor ablation, interference within the TME, and immunotherapy in one potential modality.

Biological evaluation of non-basic chalcone CYB-2 as a dual ABCG2/ABCB1 inhibitor.

The enhancement of drug efflux caused by ATP-binding cassette (ABC) transporters (including ABCG2 and ABCB1) overexpression is an important factor for multidrug resistance (MDR) in cancers. After testing the reversal activities of 19 chalcone and bis-chalcone derivatives on MDR cancer cell lines, we found that non-basic chalcone CYB-2 exhibited the most potent reversal activities against both ABCG2- and ABCB1-mediated MDR. The mechanistic studies show that this compound can increase the accumulation of anticancer drugs in both ABCG2- and ABCB1-overexpressing cancer cell lines, resulting from the blocked efflux function of the MDR cancer cell lines. This inhibition is due to the barred ABCG2 and ABCB1 ATPase activities rather than altering the expression or localization of ABCG2 or ABCB1 transporters. The previous studies showed that non-basic chalcones were ABCG2-specific inhibitors; however, we found that non-basic chalcone CYB-2 can be developed as an ABCG2/ABCB1 dual inhibitor to overcome MDR in cancers that co-express both ABCG2 and ABCB1. Moreover, non-basic chalcone CYB-2 has synthetic tractability compared to other chalcone-based derivatives.

Benzoyl indoles with metabolic stability as reversal agents for ABCG2-mediated multidrug resistance.

Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20 cells, and sensitized NCI-H460/MX20 cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs.

Aspirin Exposure and Mortality Risk among Prostate Cancer Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Prostate cancer (PCa) is the ninth most common cause of cancer death globally. Many studies have investigated aspirin exposure and mortality risk among PCa patients, returning inconsistent results. We conducted a comprehensive meta-analysis to explore the association between aspirin exposure and mortality risk among PCa patients and to investigate potential dose/duration/frequency-response relationships. METHODS AND RESULTS: Studies published from 1980 to 2018 of PubMed and EMBASE databases were searched. We included 14 studies with 110,000 participants. Multivariate-adjusted odds ratios (ORs) were pooled using random-effect models. Potential dose/duration/frequency-response relationships were evaluated for aspirin exposure and prostate cancer-specific mortality (PCSM) risk. We did not detect an association between the highest aspirin exposure and mortality risk (PCSM of prediagnostic aspirin exposure, OR: 0.96, 95% confidence interval [CI]: 0.87-1. 07, I2= 0%; PCSM of postdiagnostic aspirin exposure, OR:0.92, 95% CI: 0.77-1.10, I2 = 56.9%; all-cause mortality [ACM] of prediagnostic aspirin exposure, OR: 0.96, 95% CI: 0.88-1.04, I2 = 9.4%; ACM of postdiagnostic aspirin exposure, OR: 0.95, 95% CI: 0.73-1.23, I2 = 88.9%). There was no significant dose/frequency-response association observed for aspirin exposure and PCSM risk. On duration-response analysis, we found that short-term postdiagnostic aspirin exposure (shorter than 2.5 years) increased the risk of PCSM. CONCLUSIONS: Our meta-analysis suggests that there is no association between aspirin exposure and PCSM risk. Nor is there an association between the highest aspirin exposure and ACM risk among PCa patients. More studies are needed for a further dose/duration/frequency-response meta-analysis.

BET Inhibitors Potentiate Chemotherapy and Killing of SPOP-Mutant Colon Cancer Cells via Induction of DR5.

Bromodomain and extraterminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of a number of oncogenic proteins. Targeting this family of proteins has recently emerged as a promising anticancer approach. BET inhibitors (BETi), either alone or in combination with other anticancer agents, have exhibited efficacy in a variety of tumors. However, the molecular mechanisms underlying differential response to BETi are not well understood. In this study, we report that death receptor 5 (DR5), a key component of the extrinsic apoptotic pathway, is markedly induced in response to BRD4 depletion and BETi treatment in colorectal cancer cells. Induction of DR5, following BET inhibition, was mediated by endoplasmic reticulum stress and CHOP-dependent transcriptional activation. Enhanced DR5 induction was necessary for the chemosensitization and apoptotic effects of BETi and was responsible for increased BETi sensitivity in colorectal cancer cells containing a mutation in speckle-type POZ protein (SPOP), a subunit of BRD4 E3 ubiquitin ligase. In a colorectal cancer xenograft model, BETi combined with chemotherapy suppressed the tumor growth in a DR5-dependent manner and potently inhibited patient-derived xenograft tumor growth with enhanced DR5 induction and apoptosis. These findings suggest that BETi alone or in combination with chemotherapy is effective against colorectal cancer due to enhanced DR5 induction and apoptosis. DR5 induction may also serve as a useful marker for designing personalized treatment and improved colorectal cancer combination therapies.Significance: These findings reveal how BET inhibition sensitizes chemotherapy and kills a subset of colon cancer cells with specific genetic alterations and may provide a new molecular marker for improving colon cancer therapies.

Regorafenib antagonizes BCRP-mediated multidrug resistance in colon cancer.

Overexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silico, in vitro and in vivo. We found that regorafenib significantly sensitized MDR colon cancer cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Investigation of the mechanism revealed that regorafenib stimulated BCRP ATPase activity. Our induced-fit docking and molecular dynamics simulations suggested the existence of a strong and stable interaction between regorafenib and the transmembrane domain of human crystalized BCRP. In vivo tumor xenograft study revealed that the combination of regorafenib and topotecan exhibited synergistic effects on mitoxantrone-resistant S1-M1-80 xenograft tumors. In conclusion, our studies indicate that regorafenib would be beneficial in combating MDR in colon cancer.

Exogenous NO mediated the detoxification pathway of tomato seedlings under different stress of Cu and Cd.

Nitric oxide (NO) is a well-known signaling molecular that plays a significant role in stress tolerance of plants to heavy metals. However, the detoxification mechanism of NO has not been well studied. Here, we examined the absorbing and transporting characteristics of copper (Cu) and cadmium (Cd) in tomato seedlings through nutrient solution culture and its response to exogenous NO under Cu and/or Cd stress. Results showed that Cu and Cd with the concentration of 50 &Mgr;mol·L-1 greatly inhibited plant growth, with Cd having a higher inhibiting effect than Cu. Under single or dual stresses of Cu and Cd, their contents in both tomato roots and leaves were significantly increased. However, tomato roots showed preference to essential element Cu with a luxury uptake and strictly against Cd through cell plasma membrane in which the content of Cd was only one tenth of Cu in plants. These metal stresses, especially Cd stress, could be alleviated by application of exogenous NO. Tomato plants detoxify these passively-absorbed elements through similar mechanisms, including chelation with glutathione, phytochelatin or metallothionein, as well as vascular compartmentalization. Exogenous NO could alleviate these stresses through regulating the oxidation-reduction condition of GSH-GSSH, controlling the metabolism of GSH-PCs, as well as promoting the vascular compartmentalization of excessive Cu and Cd. In addition, NO could induce higher expression of chelators, such as MTs, GSH and PCs, in both roots and shoots, which showed additive effects to other responses and might be another important detoxification pathway mediated through NO for the responses of tomato plants to Cu and Cd stresses.

Immunogenic effects of chemotherapy-induced tumor cell death.

Emerging evidence suggests that the clinical success of conventional chemotherapy is not solely attributed to tumor cell toxicity, but also results from the restoration of immunosurveillance, which has been largely neglected in the past preclinical and clinical research. Antitumor immune response can be primed by immunogenic cell death (ICD), a type of cell death characterized by cell-surface translocation of calreticulin (CRT), extracellular release of ATP and high mobility group box 1 (HMGB1), and stimulation of type I interferon (IFN) responses. Here we summarize recent studies showing conventional chemotherapeutics as ICD inducers, which are capable of modulating tumor infiltrating lymphocytes (TILs) and reactivating antitumor immunity within an immuno-suppressive microenvironment. Such immunological effects of conventional chemotherapy are likely critical for better prognosis of cancer patients. Furthermore, combination of ICD-inducing chemotherapeutics with immunotherapy is a promising approach for improving the clinical outcomes of cancer patients.

Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial.

OBJECTIVE: There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need. DESIGN AND RESULTS: A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively. CONCLUSIONS: This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group. TRIAL REGISTRATION: NCT01770431; Post-results.

Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer.

Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by a mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC). However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we demonstrate that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. PUMA induction and p73 activation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations. Inhibition of aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction. Our results suggest that PUMA plays a critical role in meditating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA-mediated apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy.