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Colorectal cancer (CRC) remains the third most commonly diagnosed cancer, ranking second among the most common causes of cancer-related mortality. Immune checkpoint therapy has recently been shown to have great potential. However, only some patients respond to immune checkpoint blockade, indicating the unmet need for determining the underlying mechanism of colorectal cancer immunosuppression. In this study, we analyzed The Cancer Genome Atlas (TCGA) datasets and found that high expression of PIPKIγ positively correlated with tumor-associated macrophage infiltration. Further loss-of-function studies revealed that silencing PIPKIγ greatly reduced CCL2 expression at both the mRNA and protein levels, leading to weak chemotaxis of cancer cells to macrophages. Mechanistically, PIPKIγ facilitated PI3K-Akt-mTOR signaling pathway activation to increase STAT3 phosphorylation levels, thus triggering CCL2 transcription to enhance tumor-associated macrophage recruitment. These findings identify the PIPKIγ signaling pathway as a new actor in colorectal cancer immunosuppression and a potential therapeutic target for this common cancer.

Summary An elaborately designed multifunctional nanoplatform with intelligent and inherent tumor-specific theranostic capacity is urgently desired for highly efficient cancer treatments. Herein, we report a class of compact MnO2-laden black phosphorus (BPN/MnO2) nanostructure for delivering drugs with smart tumor-specific diagnosis and exquisite self-driven therapeutic features. The auxiliary MnO2 nanosheets promote the photodynamic therapy (PDT) of black phosphorus nanosheets (BPNs) by 3.8-fold through their inherent remarkable hypoxia amelioration. Moreover, BPN/MnO2 shows an obvious 37% photothermal therapy (PTT) enhancement relative to BPNs. Significantly, the multiple-tumor-microenvironment-responsive features of MnO2 contribute to the maximized drug administration on the tumor (≥4-fold drug release of the single acid stimuli), thus reducing the potential side effect of chemotherapy on normal tissues. Besides the spatiotemporally programmable administration of drugs, BPN/MnO2 also provides intelligent MRI and thermal imaging guidance for synergistically enhancing PDT, PTT, and chemotherapy, thus offering an intelligent versatile toolbox for multifunctional nanotheranostic applications.

Backgrounds: To describe the clinical characteristics of coronavirus disease 2019 hospitalized patients and further analyze the potential risk factors related to the severity of the disease and 28-day mortality of patients.Methods: A total of 122 coronavirus disease 2019 patients hospitalized in Wuhan Third Hospital from 26 January 2020 to 16 March 2020 were included in this retrospective study. Clinical data of patients were retrospectively analyzed, and the risk factors associated with disease severity and 28-day mortality were screened by cox regression analysis.Results: Of all 122 patients, the median age was 64 years old (interquartile range, 57- 71 years old).Compared with non-severe patients, severe patients had higher indices like cardiac troponin T and respiratory rate. In cox regression analysis, cardiac troponin T correlated with 28-day mortality most.Conclusions: Abnormal cardiac troponin T value after admission were in strong correlation with 28-day survival status.

Background: To investigate the role that transcription factors TWIST1, TWIST2 and PPARγ play in nonalcoholic steatohepatitis progression. Methods: The protein levels of TWIST1, TWIST2 and PPARγ were determined in the serum of NAFLD patients and healthy controls by ELISA. An in vivo model for fatty liver was established by feeding C57BL/6J mice a high fat diet (HFD). An in vitro model of steatosis was established by treating LO-2 cells with oleic acid (OA). RNA sequencing was performed on the untreated and OA treated LO-2 cells followed by TWIST1, TWIST2 and PPARγ gene mRNA levels analysis, Gene Ontology (GO) enrichment and pathway analysis. Results: The TWIST2 serum protein levels decreased significantly in all fatty liver groups (PP=0.0018). IL-17 and TNF signaling pathways were enriched in OA treated cells. Conclusions: Our results provide evidence that TWIST2 and PPARγ are important in NAFLD and shed light on a potential mechanism of steatosis.

3106 Background: WX390 is a high potent PI3K-mTOR dual inhibitor targeting pan-PI3K and mTOR. WX390 exhibited anti-tumor activity and high potency in xenograft models with inhibition of AKT phosphorylation. Methods: Patients (pts) with advanced lymphoma and solid tumors who have failed standard therapies were enrolled in dose escalation cohorts and received WX390 administered daily orally in 28-day cycles until confirmed progressive disease, intolerable toxicity or withdrawal of consent. Plasma samples were collected up to 7 days after the first dose and up to 24 hours at C1D28. Results: As of the cut-off date 2021 Feb 10, 25 patients (median age 52 years) were enrolled in 6 dose levels (0.1mg, 0.2mg, 0.4mg, 0.7mg, 1.1mg and 1.4mg) of the dose-escalation cohorts. Cohorts 0.1 mg to 1.1 mg were completed without dose-limiting toxicities (DLT), cohort 1.4 mg was completed with 1 DLT (Diabetic ketoacidosis combined with grade 3 hyperglycemia) out of 4 evaluable patients. Common treatment-related adverse events (TRAEs) (all grades, ≥20%) included hyperglycemia (20 pts, 80%), proteinuria (10 pts, 40%), creatinine increased (11 pts, 44%), hypophosphatemia (10 pts, 25%), anemia (8 pts, 33.3%), thrombocytopenia (7 pts, 29.2%), and aspartate aminotransferase increased (25%). Grade≥3 TRAEs were hyperglycemia (7 pts, 28%, 1 pt combined with diabetic ketoacidosis), hypophosphatemia (2 pts, 8%), neutropenia (2 pts, 8%), dermatitis (1 pt, 4%), and maculopapular rash (1 pt, 4%). PK showed fast absorption (Tmax 0.5-4 h) and dose proportionality for Cmax and AUC0-∞. The mean multiple dose T1/2 was approximately 12.4 hours across all cohorts with minimum accumulation. Among 14 tumor response evaluable patients, there were 3 patients with confirmed PIK3CA mutation. All 3 patients experienced tumor shrinkage and were still on treatment by the cut-off date. 2 (1 pt with head and neck cancer and 1 pt with cervical cancer) of them have achieved partial response (PR). The head and neck cancer patient (PR) was treated with WX390 0.7mg/day without any severe AE and the duration of response was beyond 15 months. Stable disease (SD) was observed in 6 patients (n = 5 with unknown PIK3CA mutation status and n = 1 with confirmed PIK3CA mutation). Of note, 1 patient (follicular lymphoma) treated with 0.1mg experienced SD for 14 months. Another patient (SD, head and neck cancer with PIK3CA mutation) experienced tumor shrinkage for more than 8 months and was still receiving WX390 treatment by the cut-off date. Conclusions: the PI3K-mTOR dual inhibitor WX390 was well tolerated with manageable safety profile, and showed encouraging antitumor activity. A RP2D of 1.1 mg qd is selected to be explored for different indications in solid tumor clinical studies. Clinical trial information: NCT03730142.

Hypoxia and dysregulation of microRNAs (miRNAs) have been identified as crucial factors in carcinogenesis. However, the potential mechanisms of HIF-1α and miR-421 in gastric cancer have not been well elucidated. In this study, we found that miR-421 was up-regulated by HIF-1α. Overexpression of miR-421 promoted metastasis, inhibited apoptosis, and induced cisplatin resistance in gastric cancer in vivo and in vitro. E-cadherin and caspase-3 were identified as targets of miR-421. Besides, relative mRNA expression of miR-421 was significantly increased in gastric cancer tumor tissues compared with non-tumor tissues in a cohort of gastric cancer specimens (n=107). The expression of miR-421 was higher in advanced gastric cancers compared with localized ones. Moreover, Kaplan-Meier analysis illustrated that those patients with low levels of miR-421 had a significant longer overall survival (p = 0.006) and time to relapse (p = 0.007). Therefore, miR-421 could serve as an important prognostic marker and a potential molecular target for therapy in gastric cancer.

We present a smartphone optosensing platform (SOP) using a digital versatile disc (DVD) diffraction grating for rapid in-field detecting neurotoxins. The smartphone holder and sample holder were 3D printed for the SOP. A DVD grating is demonstrated for the first time in a low-cost miniature spectrometer on the SOP to quantify the concentrations of neurotoxins. The SOP is capable of detecting optical absorbance spectra within the entire visible spectral range from 400 to 700 nm with the spectral resolution of 0.2521 nm/pixel. We demonstrated the performance of the DVD grating compared with a commercial transmission grating on the SOP and a conventional microplate reader. Paraoxon, as the selected neurotoxin model, is assayed by two types of cholinesterase (ChE) on our SOP, respectively. Integrating a DVD grating in the SOP allows quantification of paraoxon in the range from 5 nM to 25 μM with the detection limit of 2.9 nM. In addition to the low assessed detection limit at medically relevant concentrations...

Cytokine-induced killer (CIK) cells represent a realistic approach in cancer immunotherapy with confirmed survival benefits in the context of metastatic solid tumors. However, therapeutic effects are limited to a fraction of patients. In this study, immune-resistance elements and ideal combination therapies were explored. Initially, phenotypic analysis was performed to document CD3, CD56, NKG2D, DNAM-1, PD-L1, PD-1, CTLA-4, TIM-3, 2B4, and LAG-3 on CIK cells. Upon engagement of CIK cells with the tumor cells, expression of PD-1 on CIK cells and PD-L1 on both cells were up-regulated. Over-expression of PD-L1 levels on tumor cells via lentiviral transduction inhibited tumoricidal activity of CIK cells, and neutralizing of PD-L1/PD-1 signaling axis could enhance their tumor-killing effect. Conversely, blockade of NKG2D, a major activating receptor of CIK cells, largely caused dysfunction of CIK cells. Functional study showed an increase of NKG2D levels along with PD-L1/PD-1 blockade in the presence of other immune effector molecule secretion. Additionally, combined therapy of CIK infusion and PD-L1/PD-1 blockade caused a delay of in vivo tumor growth and exhibited a survival advantage over untreated mice. These results provide a preclinical proof-of-concept for simultaneous PD-L1/PD-1 pathways blockade along with CIK infusion as a novel immunotherapy for unresectable cancers.

TPS1101 Background: MRG002 is an antibody drug conjugate (ADC) composed of a humanized anti-HER2 IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG002 is presently being investigated in an ongoing phase I study for safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity in patients (pts) with solid tumors. Methods: MRG002 is evaluated as monotherapy for the treatment of pts with confirmed HER2 positive locally advanced or metastatic cancers, including breast cancer (BC), gastric cancer (GC), salivary gland cancer (SGC) and others. The primary objective is to determine the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D). Secondary objectives include evaluation of PK, tumor response, and immunogenicity. In the dose escalation phase with “3+3” design, approximately 24 pts will be enrolled to identify MTD. The starting dose of MRG002 is 0.3 mg/kg, followed by 0.6, 1.2, 1.8, 2.2, 2.6, and 3.0 mg/kg. In the dose expansion phase, about 50 pts with HER2 positive advanced cancers will be enrolled to further evaluate the safety, antitumor activity, and PK at an appropriate confirmed dose. In this phase I study, each pt receives single agent MRG002 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. Pts with BC and GC should have HER2 positive advanced solid tumors per College of American Pathologists (CAP) guidelines. For other cancers, pts must have IHC status of 2+ or 3+, regardless of FISH results. Pts should have either failed or are ineligible for standard treatments. All pts must have at least 1 measurable lesion per RECIST 1.1. ECOG should be 0-1, and bone marrow, hepatic, renal, cardiac functions should be adequate. Observations include adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity, which is assessed every two treatment cycles. Further clinical trial details can be found on chinadrugtrials.org.cn (CTR20181778). Enrollment is ongoing since November 2018. Clinical trial information: CTR20181778 .

3638 Background: Bone is one of the most common metastatic sites of malignancies. The metastatic tumor cells activate osteoclast activity and promote bone resorption via RANKL/RANK signaling pathway, and lead to osteolytic destruction. JMT103 is an innovative fully human IgG4 monoclonal antibody targeting RANKL. It can block RANKL/RANK signaling pathway, inhibit bone resorption, and protect bones from tumor metastasis. This study aimed to evaluate the safety and tolerability of JMT103 in patients with bone metastasis. Methods: This is a multi-center, open label, dose escalation, phase I clinical trial. The patients (ECOG score: 0-1) with bone metastasis from solid tumor who had not received bisphosphonates within 6 weeks before enrollment and were naïve to denosumab were enrolled. The initial dose was 0.5 mg/kg, sequentially escalated to 1.0, 2.0, and 3.0 mg/kg. JMT103 was injected subcutaneously by accelerated titration in 0.5 and 1.0 mg/kg dose groups, but via traditional "3+3" dose-escalation design in 2.0 and 3.0 mg/kg dose groups. Expansion study was conducted for subjects in 1.0, 2.0, and 3.0 mg/kg dose groups. Specifically, 3 additional doses (q4w) were injected after the end of 12-week single-dose study. The primary endpoints were maximum tolerated dose and safety. The secondary outcome measures included PK profile, preliminary efficacy biomarkers, immunogenicity, and bone mineral density (BMD). Results: From May 2018 to January 2020, 56 patients (13 males, 43 females, mean (SD) age: 55.57 (11.42) years) were enrolled, including bone metastasis from breast cancer (n = 36), gastric cancer (n = 5), lung cancer (n = 4), rectal cancer (n = 3), colorectal cancer (n = 2), or other solid tumors (n = 6). Nineteen patients participated in the dose-escalating study and 37 patients participated in the expansion study. JMT103 showed overall good safety. There were 74 drug-related AEs in all, including grade 3 (DLT hypocalcemia, n = 1; hypophosphatemia, n = 3), grade 2 (n = 15), and grade 1 (n = 55) AEs. The most common drug-related AEs were hypophosphatemia (n = 15), hypocalcemia (n = 12), and hypermagnesemia (n = 6). Median uNTx/Cr decrease from baseline was 76.6% (n = 20). Conclusions: JMT103 shows good safety and tolerability in patients with bone metastasis. Clinical trial information: NCT03550508 .

// Jinjia Chang 1,* , Shanshan Wang 1,* , Zhe Zhang 1 , Xinyang Liu 1 , Zheng Wu 1 , Ruixuan Geng 1 , Xiaoxiao Ge 1 , Congqi Dai 1 , Rujiao Liu 1 , Qunling Zhang 1 , Wenhua Li 1 and Jin Li 1 1 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China * These authors contributed equally to this work Correspondence: Jin Li, email: // Keywords : drug resistance, gastric cancer, AZD4547, FGFR2 Received : September 16, 2014 Accepted : December 09, 2014 Published : December 10, 2014 Abstract Fibroblast growth factor receptor 2 (FGFR2)-targeted therapy has attracted considerable attention as novel anticancer agents in gastric cancer (GC). However, intrinsic or acquired drug resistance has emerged as a major challenge to their clinical use. In this study, we demonstrated that several receptor tyrosine kinase (RTK), including EGFR, HER3 and MET, activations contributed to AZD4547 (a selective FGFR2 inhibitor) hyposensitivity in FGFR2 amplified GC cells. The rescue effect was abrogated by inhibiting these RTKs with their targeted tyrosine kinase inhibitors (TKIs). In addition, synergy in growth inhibition was observed when the GC cells were treated with a combination of AZD4547 and cetuximab (an EGFR monoclonal antibody) both in vitro and in vivo . More importantly, tissue microarray analysis revealed that these resistance-conferring RTKs were highly expressed in FGFR2 positive GC patients. Taken together, these observations demonstrated RTKs including EGFR, HER3 and MET activations as novel mechanisms of hyposensitivity to AZD4547. It will be clinically valuable to investigate the involvement of RTK-mediated signaling in intrinsicor acquired resistance to FGFR2 TKIs in GC. A combination targeted therapeutic strategy may be recommended for treating FGFR2 amplified GC patients with these RTK activations.

Crizotinib has been reported to be particularly effective and to have acceptable toxicity in advanced anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC). In this study, we analyzed the efficacy and tolerability of crizotinib in the treatment of 72 Chinese patients with ALK-positive, advanced NSCLC. All patients received oral crizotinib 250 mg twice daily in 28-day cycles during the period June 1, 2013, to October 15, 2014. The tumor response was assessed after the first cycle of crizotinib and then after every two cycles using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Tolerability was assessed at least twice per cycle until crizotinib was discontinued. The patients tended to be young (mean age 55 years, range 31–83 years), never or light smokers (smoking index

Despite the promising results from initial studies, there are significant limitations in the application of MET-targeted therapy in gastric cancer. Intrinsic resistance is one of the major obstacles. The aim of this study is to identify the responsible receptor tyrosine kinases (RTKs) that determine the unresponsiveness of MET inhibitor in MET-positive gastric cancer. through an RNA-interference-based functional screen targeting most human RTKs, we identified that activation of the fibroblast growth factor receptor 2 (FGFR2) and recepteur d'origine nantais (RON) pathways attenuated MET inhibitor-induced suppression of cell proliferation and migration. Notably, in the two forms of RON pathway activation, only upregulation of short-form RON (sf-RON), but not stimulation of full length RON with macrophage stimulating protein, conferred MET inhibitor resistance in vitro and in vivo. Furthermore, the profile of the gastric cancer samples observed that sf-RON was frequently upregulated in MET-positive gastric cancer. Our findings indicate that activation of the sf-RON signaling pathway represents a novel mechanism underlying MET inhibitor unresponsiveness. A combination strategy with drugs targeting both RON and MET pathways is believed to improve the efficacy of MET-targeted therapy.

To evaluate the insulin receptor isoform mRNA expression status in NSCLC patients RNA-seq data from 614 NSCLC [355 adenocarcinomas(LUAD) and 259 squamous cell carcinomas (LUSC)] and 92 normal lung specimens were obtained from The Cancer Genome Atlas (TCGA) to evaluate the mRNAexpression of insulin receptor isoform A (IR-A) and insulin receptor isoform B(IR-B). The differential expression status of the insulin receptor isoforms in NSCLC patients was confirmed using qRT-PCR assays with lung cancer cDNA arrays and primary tumor samples. The mRNA expression levels of IR-B were significantly lower in some NSCLC samples compared to normal lung specimens,including both LUAD and LUSC. Notably, no IR-B transcripts were detected - only the IR-A isoform was expressed in 11% of NSCLC patients. This decrease in IR-B expression contributed to an elevated IR-A/IR-B ratio, which was also associated with lower epithelial-mesenchymal transition gene signatures in NSCLC and longer patient survival under standard of care in LUSC. In addition to NSCLC, RNA-seq data from TCGA revealed a similar increase in IR-A/IR-B ratio in many other cancer types, with high prevalence in acute myeloid leukemia,glioblastoma multiforme, and brain lower grade glioma. Our results indicate a common reduction of the mRNA expression level of IR-B and an increased IR-A/IR-B mRNA ratio in NSCLC and other tumor types. The relationship of altered IR-A/IR-B ratios with cancer progression and patient survival should be prospectively explored in future studies. Citation Format: Jiaqi Huang, Wei Zhu, Liyan Jiang, Katie Streicher, Chris Morehouse, Philip Brohawn, XiaoXiao Ge, Zhengwei Dong, Xiaolu Yin, Guanshan Zhu, Yi Gu, Parthiv Mahadevia, Brandon W. Higgs, Yihong Yao. Increased IR-A/IR-B ratio in non-small cell lung cancers associates with lower epithelial-mesenchymal transition signature and longer survival in squamous cell lung carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4909. doi:10.1158/1538-7445.AM2015-4909

Intratumor heterogeneity can confound the results of mutation analyses in oncodriver genes using traditional methods thereby challenging the application of targeted cancer therapy strategies for patients. Ultradeep sequencing can detect low frequency and expanded clonal mutations in primary tumors to better inform treatment decisions. KRAS coding exons in 61 treatment-naïve colorectal cancer (CRC) tumors and KRAS, EGFR, ALK, and MET in lung tumors from three Chinese non-small cell lung cancer (NSCLC) patients were sequenced using ultradeep sequencing methods. Forty-one percent of CRC patients (25/61) harbored mutations in the KRAS active domain, eight of which (13%) were not detected by Sanger sequencing. Three (of eight) had frequencies less than 10% and one patient harbored more than one mutation. Low frequency KRAS active (G12R) and EGFR kinase domain mutations (G719A) were identified in one NSCLC patient. A second NSCLC patient showed an EML4-ALK fusion with ALK, EGFR, and MET mutations. A third NSCLC patient harbored multiple low frequency mutations in KRAS, EGFR, and MET as well as ALK gene copy number increases. Within the same patient, multiple low frequency mutations occurred within a gene. A complex pattern of intrinsic low frequency driver mutations in well-known tumor oncogenes may exist prior to treatment, resulting in resistance to targeted therapies. Current targeted cancer therapies usually lack durability and demonstrate limited overall efficacy in patients. The types of low frequency concurrent mutations in candidate oncogenes presented here suggest necessary modifications both to methods for detection of these variants and to general treatment strategies. To date, Sanger sequencing has been effectively used for detection of treatment-relevant somatic mutations. However, in a heterogeneous mixture of cancerous and normal tissue, Sanger sequencing will likely fail to detect low frequency mutations. More sensitive and cost-effective sequencing methods are required to systematically assess the mutation status within cancer pathway genes or at the whole genome level. Furthermore, because patients often develop resistance to targeted therapy over time that is due to the preexistence of low frequency mutations in oncogenes, treatment strategies based on combination therapy might prove to be the most optimal treatment approach for cancer patients. Ultradeep sequencing can characterize intratumor heterogeneity and identify such mutations to ultimately affect treatment decisions. Citation Format: Christopher Morehouse, Liyan Jiang, Jiagi Huang, Wei Zhu, Susana Korolevich, Xiaoxiao Ge, Kim Lehmann, Zheng Lui, Christine Kiefer, Meggan Czapiga, Xinying Su, Philip Brohawn, Yi Gu, Brandon Higgs, Yihong Yao. Low frequency KRAS mutations in colorectal cancer patients and the presence of multiple mutations in oncogenic drivers in non-small cell lung cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2377. doi:10.1158/1538-7445.AM2014-2377

Introduction: Salivary gland–type cancers are rare lung neoplasms involving mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), and epithelial–myoepithelial carcinoma (EMC). Their behavior and prognostic features are not clearly defined because of their low incidence. We retrospectively analyzed the clinicopathologic profiles of these tumors in a large series. Methods: Eighty-eight patients confirmed as having primary salivary gland–type lung cancer between May 2001 and January 2013 were included from the archives of two thoracic oncology center institutions in China and retrospectively evaluated. Results: Of the total 88 patients, 69 were MEC, 12 ACC, and seven EMC. Overall survival (OS) at 3, 5, and 10 years was 91.3%, 86%, and 80.6% in all cases, respectively, and disease-free survival (DFS) was 90.1%, 78.6%, and 55%, respectively. No significant difference was found among MEC, ACC, and EMC groups regarding OS (p = 0.518) and DFS (p = 0.082). Tumor-node-metastasis stage, lymph node involvement, intrathoracic invasion, and margin status were found to be related with OS (p = 0.000, 0.029, 0.000, 0.004) and DFS (p = 0.018, 0.042, 0.002, 0.002). Intrathoracic invasion was an independent predictor for OS (hazard ratio [HR], 1.129; p = 0.039) and DFS (HR, 1.071; p = 0.011). For patients with MEC, pathological grade also was an independent predictor of OS (HR, 0.045; p = 0.006) and DFS (HR, 0.067; p = 0.001). Conclusions: Salivary gland–type lung cancers are a group of low-aggressive entities with higher tendency to recurrence/metastasis. Intensive clinical, radiological, and pathological examinations are essential to estimation of the risk stratification and management.

Background To evaluate the insulin receptor isoform mRNA expression status in non-small cell lung cancer (NSCLC) patients. Methods RNA-seq data from 614 NSCLC [355 adenocarcinomas (LUAD) and 259 squamous cell carcinomas (LUSC)] and 92 normal lung specimens were obtained from The Cancer Genome Atlas (TCGA) to evaluate the mRNA expression of insulin receptor isoform A (IR-A) and insulin receptor isoform B (IR-B). The differential expression status of the insulin receptor isoforms in NSCLC patients was confirmed using qRT-PCR assays with lung cancer cDNA arrays and primary tumor samples. Results The mRNA expression levels of IR-B were significantly lower in some NSCLC samples compared to normal lung specimens, including both LUAD and LUSC. Notably, no IR-B transcripts were detected - only the IR-A isoform was expressed in 11% of NSCLC patients. This decrease in IR-B expression contributed to an elevated IR-A/IR-B ratio, which was also associated with lower epithelial-mesenchymal transition gene signatures in NSCLC and longer patient survival under standard of care in LUSC. In addition to NSCLC, RNA-seq data from TCGA revealed a similar increase in IR-A/IR-B ratio in many other cancer types, with high prevalence in acute myeloid leukemia, glioblastoma multiforme, and brain lower grade glioma. Conclusions Our results indicate a common reduction of the mRNA expression level of IR-B and an increased IR-A/IR-B mRNA ratio in NSCLC and other tumor types. The relationship of altered IR-A/IR-B ratios with cancer progression and patient survival should be prospectively explored in future studies.