Multiple myeloma (MM) was characterized by frequent mutations in KRAS/NRAS/BRAF within the EGFR pathway that could induce resistance to EGFR inhibitors. We here report that EGFR inhibition solely exhibited moderate inhibition in KRAS/NRAS/BRAF wildtype (triple-WT) MM cells, whilst had no effect in myeloma cells with any of the mutated genes. The moderate inhibitory effect was conferred by induction of pentose phosphate pathway (PPP) when cells were treated with Gefitinib, the EGFR inhibitor. Combination of Gefitinib with PPP inhibitor 6AN effected synergistically in triple-WT cells. The inhibition could be restored by addition of NADPH. Dual EGFR/ERBB2 inhibitor Afatinib also exhibited similar effects. Further genetic silencing of EGFR, ERBB2 and mTOR indicated that major effect conferred by ERBB2 was via convergence to EGFR pathway in MM. Our results contributed to the individualized targeted therapy with EGFR inhibitors in MM.

Beclin 1, a key regulator of autophagy, has been found to be aberrantly expressed in a variety of human malignancies. Herein, we employed immunohistochemistry (IHC) to detect the protein expression of Beclin 1 in non-small cell lung cancer (NSCLC) and paired normal adjacent lung tissues, and analyzed its clinicopathological/prognostic significance in NSCLC. Receiver operating characteristic (ROC) curve analysis was utilized to determine a cutoff point (>2 VS. ≤2) for Beclin 1 expression in a training set (n = 105). For validation, the ROC-derived cutoff value was subjected to analysis of the association of Beclin 1 with patients’ clinical characteristics and outcome in a testing set (n = 111) and the overall patient cohort (n = 216). Our data showed that Beclin 1 was significantly lower in NSCLC tissues compared with the adjacent normal tissues, negatively associating with tumor recurrence rate (65.8% VS 32.3%; p < 0.001). In the testing set and the overall patient cohort, low expression of Beclin 1 showed significantly inferior overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) compared to high expression of Beclin 1. In the testing set and the overall patient cohort, the median duration of OS for patients with high and low expression of Beclin 1 was 108 VS. 24.5 months (p < 0.001) and 108 VS. 28 months (p < 0.001), respectively. Furthermore, low expression of Beclin 1 was also a poor prognostic factor within each stage of NSCLC patients. Multivariate analysis identified that Beclin 1 was an independent prognostic factor for NSCLC. Our findings in the present study provided evidence that Beclin 1 may thus emerge as an independent prognostic biomarker in this tumor entity in the future.

To identify the clinical features of lymphoma-associated hemophagocytic syndrome (LAHS), we retrospectively analyzed the clinical characteristics, laboratory findings and survival data of 16 LAHS patients from 69 adult hemophagocytic syndrome (HPS) patients. The results showed that the most common clinical manifestations and laboratory parameters were fever (100%), ferritin ≥ 500 g/L (100%), peripheral cytopenia in two or more lineages (100%), fibrinogen (Fbg) < 1.5 g/L (93.8%) and splenomegaly (81.3%) in LAHS patients. The percentages of patients with Fbg < 1.5 g/L, PLT < 40 × 10(9)/L and LDH ≥ 1,000 U/L in the LAHS group were significantly higher than those in non-LAHS patients (P = 0.010, 0.000, and 0.001, respectively). Survival analysis showed that HLH patients with rheumatological reasons had better prognosis (OS; median not reached), followed by patients in the infection group (350 days) and those with unexplained causes (140 days). LAHS had the worst prognosis (only 37 days). The symptoms of LAHS patients are usually confused with other HPS. Patients with LAHS had higher probabilities to have Fbg < 1.5 g/L, PLT < 40 × 10(9)/L, LDH ≥ 1,000 U/L and poor prognosis, so early diagnosis and systemic treatments are required.

Pentose phosphate pathway (PPP) is a metabolic pathway that generates NADPH and pentose. PPP genes have been reported to be primarily or secondarily upregulated in many cancers. We aimed to study the general alteration of PPP in acute myelogenous leukemia (AML). We performed data mining and analysis of the Cancer Genome Atlas (TCGA) AML dataset for genetic alteration of the PPP gene set. In vitro studies including proliferation, migration, and invasion assays, together with metabolite consumption and oxidation assays, were performed. PPP genes were upregulated in 61 % of patients with AML. The majority of altered cases were expression changes measured by RNA sequencing. Expressions of critical PPP genes such as G6PD, PFKL, PFKP, and PGLS were consistently upregulated in all altered cases. Altered PPP is not associated with survival or disease relapse. PPP inhibition using 6-aminonicotinamide (6AN) increases glucose oxidative metabolism in AML. 6AN decreased the glucose oxidation and increased fatty acid oxidation. Here, we showed that PPP inhibition increased glucose oxidative metabolism in AML. PPP inhibition suppressed growth, migration, and invasion of AML, but not colony formation. PPP plays an important role in AML. Our results could contribute to the development of novel targeted treatment.

of detection) did not identify an aberrant clonal plasma cell population in this patient.We conclude that for select patients with clinical features of systemic AL amyloidosis (ie, heart failure with preserved ejection fraction, proteinuria, unexplained hepatomegaly, and axonal demyelinating peripheral neuropathy), the absence of monoclonal gammopathy should not deter aspiration of subcutaneous fat and/or tissue biopsy of the affected organ. Only histopathological analysis for Congophilia and accurate precursor protein typing can lead to diagnosis in some cases. Moreover, it is important to distinguish these systemic cases from localized AL amyloidosis, which does not require systemic chemotherapy.The authors declare no competing conflicts of interest. AUTHOR CONTRIBUTIONSAS collected and analyzed data, and wrote the manuscript in consultation with YK, DJM and JMS; VS edited and revised the final version.

Background/Aims: CyclinG1 (CycG1) is frequently overexpressed in solid tumors and overexpression of CycG1 promotes cell survival upon paclitaxel exposure by inducing polyploidy. Whether and how CycG1 regulates polyploidization caused by small molecular targeted inhibitors remains unclear. Methods: Immunohistochemistry and immunoblotting were utilized to examine protein expression. Cell proliferation was measured by ATPlite assay, and cell cycle distribution and apoptosis were measured by flow cytometry and/or DNA fragmentation assays. Results: Overexpression of CycG1 in breast cancer cells caused apoptosis-resistant polyploidy upon treatment with Aurora kinase inhibitor, ZM447439 (ZM). Addition of ABT-263, a small-molecule BH3 mimetic, to ZM, produced a synergistic loss of cell viability with greater sustained tumor growth inhibition in breast cancer cell lines. Decrease of Mcl-1 and increase of NOXA caused by ZM treatment, were responsible for the synergy. Furthermore, CycG1 was highly expressed in Triple-Negative-Breast-Cancer patients treated with paclitaxel and was paralleled by decreased cell survival. Conclusion: CycG1 is a crucial factor in ZM-induced polyploidy resistance, and ABT-263/ZM combination hold therapeutic utility in the CycG1-amplified subset of breast cancer and CycG1, thus, is a promising target in breast cancer.

No abstract

Background: Primary immune thrombocytopenia (ITP) is characterized by increased platelet destruction and impaired platelet production, resulting in decreased platelet counts and increased bleeding risk. Spleen Tyrosine Kinase (Syk) plays a pivotal role in the regulation of downstream signals in immune receptors, including B cell receptors (BCRs) and has been implicated in autoantibody production. On the other hand, all activating Fc receptors signal via Syk, which has roles in cellular proliferation, differentiation, survival, immune regulation, and cytoskeletal rearrangements during phagocytosis. This randomized, double-blind, placebo-controlled phase 1b study (NCT03951623) aimed to assess the safety, pharmacokinetics (PK), determine the recommended phase 2 dose (RP2D) and evaluate preliminary efficacy of HMPL-523, a novel, potent and highly selective Syk inhibitor, in patients with ITP. Methods: Relapsed/refractory ITP patients with platelet counts less than 30×10 9/L were eligible for the study. This randomized study (3:1) consists of two stages with dose escalation (DES) and dose expansion (DEX). Four dose groups were set (100, 200, 300 and 400mg QD) and patients were randomized to either HMPL-523 or placebo in each dose group (n=8) to determine the RP2D in DES. Additional 12 patients were enrolled at RP2D to further assess the safety and efficacy in DEX. Each patient received an 8-week double blind treatment (8w-DB), followed by a 16-week, open-label HMPL-523 treatment (16w-OL), except for all patients of 100mg cohort and 2 patients of 200mg cohort (only received 8w-DB per protocol v1.0). Treatment-emergent adverse events were graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0. The efficacy of overall response rate was defined as the proportion of patients with at least one platelet counts ≥50×10 9/L, and durable response rate was defined as the proportion of patients with platelet counts ≥50×10 9/L for at least 4 of the last 6 scheduled visits. Results: As of data cutoff (June 23, 2021), 33 patients (24:9) were enrolled in DES at 100-400mg. And 300mg QD was determined as RP2D. Additional 12 patients (10:2) were enrolled in DEX at 300mg QD. Main baseline patient characteristics are shown in Table 1. During 8-w DB treatment period, the overall response rate was 3 (50.0%), 2 (33.3%), 11 (68.8%) and 2 (33.3%) at 100-400mg dose cohorts, respectively, compared to 1 (9.1%) in the placebo. The durable response rate at 300mg was 5 (31.3%), compared to 1 (9.1%) in placebo. For all patients enrolled in 300mg cohort with at least one dose of HMPL-523 (n=20), including both 8w-DB and 16w-OL treatment period, the overall response rate was 80%; the durable response rate was 27.8% in the durable response-evaluable set (defined as patients received HMPL-523 treatment and completed at least 6 scheduled visits or discontinued during HMPL-523 treatment, n=18). No DLTs were observed at 100-400mg dose cohorts. The most common TEAEs (≥2 patients) related with HMPL-523 in 8w-DB were LDH increased (6 [17.6%]), ALT increased (5 [14.7%]), amylase increased (5 [14.7%]), AST increased (4 [11.8%]), neutrophil count decreased (3 [8.8%]), hypokalemia (3 [8.8%]), urine protein detection (3 [8.8%]), WBC count decreased (3 [8.8%]), gamma-glutamyl transferase (2 [5.9%]), asthenia (2 [5.9%]), dizziness (2 [5.9%]), total bile acid increased (2 [5.9%]), diarrhea (2 [5.9%]), abdominal pain (2 [5.9%]), hypertriglyceridemia (2 [5.9%]) and hyperlipidemia (2 [5.9%]). For all patients enrolled in 300mg cohort (n=20) throughout HMPL-523 treatment period (up to 24 weeks), ALT increased (5 [25.0%]), LDH increased (5 [25.0%]), AST increased (4 [20.0%]), total bile acid increased (4 [20.0%]), amylase increased (3 [15.0%]), TBiL increased (2 [10.0%]), hyperlipemia (2 [10.0%]) and hypertension (2 [10.0%]) were the most frequently reported HMPL-523-related TEAEs (≥2 patients). At the dose of 100-400mg QD, the exposure of HMPL-523 (C max and AUC tau) in plasma increased dose proportionally. Median T max was 4 h and mean T 1/2 was 11-13 h across all four dose levels. Conclusion: HMPL-523 was well tolerated at all dose levels within the range of 100 mg to 400 mg. HMPL-523 300mg QD for ITP treatment is an efficacious and safe dose and recommended as RP2D. A randomized phase 3 study will commence to further confirm the efficacy of HMPL-523 in primary ITP. Figure 1 Figure 1. Disclosures Shi: HUTCHMED: Current Employment. Yin: HUTCHMED: Current Employment. Fan: Hutchmed: Current Employment.