<img height="1" width="1" src="https://www.facebook.com/tr?id=1582471781774081&amp;ev=PageView &amp;noscript=1">
  • Menu
  • crown-logo-symbol-1-400x551

Find it Quickly

Get Started

Select the option that best describes what you are looking for

  • Services
  • Models
  • Scientific Information

Search Here For Services

Click Here to Start Over

Search Here For Models

Click Here to Start Over

Search Here For Scientific Information

Click Here to Start Over

In Vitro

Boost oncology drug discovery with XenoBase®, featuring the largest cell line selection and exclusive 3D organoid models. Benefit from OrganoidXplore™ and OmniScreen™ for rapid, in-depth analysis.

Learn More

In Vivo

Enhance drug development with our validated in vivo models, in vitro/ex vivo assays, and in silico modeling. Tailored solutions to optimize your candidates.

Learn More

Tissue

Experience ISO-certified biobanking quality. Access top biospecimens from a global clinical network, annotated by experts for precise research.

Learn More

Biomarkers and Bioanalysis

Leverage our global labs and 150+ scientists for fast, tailored project execution. Benefit from our expertise, cutting-edge tech, and validated workflows for reliable data outcomes.

Learn More

Data Science and Bioinformatics

Harness your data and discover biomarkers with our top bioinformatics expertise. Maximize data value and gain critical insights to accelerate drug discovery and elevate projects.

Learn More

KRAS

Accelerate innovative cancer treatments with our advanced models and precise drug screening for KRAS mutations, efficiently turning insights into clinical breakthroughs.

Learn More

EGFR

Advance translational pharmacology with our diverse pre-clinical models, robust assays, and data science-driven biomarker analysis, multi-omics, and spatial biology.

Learn More

Drug Resistance

Our suite integrates preclinical solutions, bioanalytical read-outs, and multi-omics to uncover drug resistance markers and expedite discovery with our unique four-step strategy.

Learn More

Patient Tissue

Enhance treatments with our human tumor and mouse models, including xenografts and organoids, for accurate cancer biology representation.

Learn More

Target to Lead Selection for ADCs and Biologics

Journey through the drug discovery pipeline from target discovery to in vivo pharmacology. Take advantage of the Largest biobank of patient-derived models, Model development capabilities, Cell-based assays for Screening ADCs, and advanced downstream analysis.

Learn More

Bioinformatics

Apply the most appropriate in silico framework to your pharmacology data or historical datasets to elevate your study design and analysis, and to improve your chances of clinical success.

Learn More

Biomarker Analysis

Integrate advanced statistics into your drug development projects to gain significant biological insight into your therapeutic candidate, with our expert team of bioinformaticians.

Learn More

CRISPR/Cas9

Accelerate your discoveries with our reliable CRISPR solutions. Our global CRISPR licenses cover an integrated drug discovery platform for in vitro and in vivo efficacy studies.

Learn More

Genomics

Rely on our experienced genomics services to deliver high quality, interpretable results using highly sensitive PCR-based, real-time PCR, and NGS technologies and advanced data analytics.

Learn More

In Vitro High Content Imaging

Gain more insights into tumor growth and disease progression by leveraging our 2D and 3D fluorescence optical imaging.

Learn More

Mass Spectrometry-based Proteomics

Next-generation ion mobility mass spectrometry (MS)-based proteomics services available globally to help meet your study needs.

Learn More

Ex Vivo Patient Tissue

Gain better insight into the phenotypic response of your therapeutic candidate in organoids and ex vivo patient tissue.

Learn More

Spatial Multi-Omics Analysis

Certified CRO services with NanoString GeoMx Digital Spatial Profiling.

Learn More

Biomarker Discovery

De-risk your drug development with early identification of candidate biomarkers and utilize our biomarker discovery services to optimize clinical trial design.

Learn More

DMPK Services

Rapidly evaluate your molecule’s pharmaceutical and safety properties with our in vivo drug metabolism and pharmacokinetic (DMPK) services to select the most robust drug formulations.

Learn More

Efficacy Testing

Explore how the novel HuGEMM™ and HuCELL™ platforms can assess the efficacy of your molecule and accelerate your immuno-oncology drug discovery programs.

Learn More

Laboratory Services

Employ cutting-edge multi-omics methods to obtain accurate and comprehensive data for optimal data-based decisions.

Learn More

Pharmacology & Bioanalytical Services

Leverage our suite of structural biology services including, recombinant protein expression and protein crystallography, and target validation services including RNAi.

Learn More

Screens

Find the most appropriate screen to accelerate your drug development: discover in vivo screens with MuScreen™ and in vitro cell line screening with OmniScreen™.

Learn More

Toxicology

Carry out safety pharmacology studies as standalone assessments or embedded within our overall toxicological profiling to assess cardiovascular, metabolic and renal/urinary systems.

Learn More

Preclinical Consulting Services

Learn more about how our consulting services can help to support your journey to the clinic.

Learn More

Our Company

Global CRO in California, USA offering preclinical and translational oncology platforms with high-quality in vivo, in vitro, and ex vivo models.

Learn More

Our Purpose

Learn more about the impact we make through our scientific talent, high-quality standards, and innovation.

Learn More

Our Responsibility

We build a sustainable future by supporting employee growth, fostering leadership, and exceeding customer needs. Our values focus on innovation, social responsibility, and community well-being.

Learn More

Meet Our Leadership Team

We build a sustainable future by fostering leadership, employee growth, and exceeding customer needs with innovation and social responsibility.

Learn More

Scientific Advisory Board

Our Scientific Advisory Board of experts shapes our strategy and ensures top scientific standards in research and development.

Learn More

News & Events

Stay updated with Crown Bioscience's latest news, achievements, and announcements. Check our schedule for upcoming events and plan your visit.

Learn More

Career Opportunities

Join us for a fast-paced career addressing life science needs with innovative technologies. Thrive in a respectful, growth-focused environment.

Learn More

Scientific Publications

Access our latest scientific research and peer-reviewed articles. Discover cutting-edge findings and insights driving innovation and excellence in bioscience.

Learn More

Resources

Discover valuable insights and curated materials to support your R&D efforts. Explore the latest trends, innovations, and expertly curated content in bioscience.

Learn More

Blogs

Explore our blogs for the latest insights, research breakthroughs, and industry trends. Stay educated with expert perspectives and in-depth articles driving innovation in bioscience.

Learn More

  • Platforms
  • Target Solutions
  • Technologies
  • Service Types

Combating Cancer Drug Resistance with In Vivo Models

Drug resistance to cancer therapy is a significant problem facing patients. It has been identified as the major factor limiting greater treatment success.

The problem is multifaceted, but one path for overcoming drug resistance and targeting drug-resistant cancers is to leverage cancer drug-resistant in vivo cell-derived xenograft (CDX) models.

In this post, we explore how such models can help researchers better understand the mechanisms of drug resistance and support the development of combination or next-generation cancer therapies.

The Problem of Cancer Drug Resistance

Cancer is a highly dynamic disease with multiple determinants that can lead to drug resistance. While therapeutic strategies have certainly reduced the consequences of drug resistance, additional approaches to challenge resistance are still urgently needed.

For example, non-small-cell lung carcinoma (NSCLC) patients with EGFR-activating mutations (i.e., exon 19 kinase domain deletions) often acquire resistance to EGFR tyrosine kinase inhibitors (TKIs). This generally results in disease progression after one year of treatment with first- or second-generation EGFR TKIs.

Although this has led to the development of multiple generations of EGFR TKIs, drug resistance continues to affect even third-generation TKIs. Relapsed patients often develop a secondary EGFR mutation (T790M) that inhibits TKIs from binding to EGFR. This is in contrast to the fewer than 5% of relapses involving mutations in PIK3CA (a downstream signaling lipid kinase).

Despite the challenges, researchers continue to make great progress by studying the mechanisms behind acquired resistance, to develop and test therapeutic strategies that exploit weaknesses of drug-resistant cancers. We will explain below why in vivo cancer drug-resistant models provide a strong platform for preclinical efficacy testing.

Options for Drug-Resistant In Vivo Models for Preclinical Efficacy Testing

Before selecting a drug-resistant in vivo model, researchers should consider the type of xenograft best suited for their study objectives.

As described in a previous blog, patient-derived xenograft (PDX) models are very useful for studying cancer drug resistance because they closely recapitulate the phenotypic and genetic features of patient tumors and have clinically relevant tumor microenvironments. Researchers can use PDXs with known drug resistance, and alternatively, resistance can be induced via genetic engineering or through repeated in vitro challenges to treatment.

Similarly, CDXs are highly suitable for developing important in vivo drug-resistant models. For instance, first-generation EGFR-TKI-resistant models were developed by establishing a drug-resistant cell line by in vitro selection. These cells were then used to establish a drug-resistant CDX in vivo model.

Specifically, the HCC827 (NSCLC EGFR tyrosine kinase deletion) cell line was repeatedly challenged with increasing concentrations of erlotinib or gefitinib, resulting in two resistant cell lines (HCC827-ER1 and HCC827-GR1).

Characterization of these new cell lines showed that both had increased copy numbers of c-MET and expression of Axl compared to the parental HCC827 cells. In vivo validation of drug resistance was confirmed by subcutaneously implanting the HCC827-ER1 cell line into nude mice (MF1-nu/nu).

In Figure 1, erlotinib was very effective in inhibiting tumor growth in “wild-type” cells (yellow plot) but much less effective in preventing the growth of the HCC827-ER1 CDX (blue plot).

Figure 1: In vivo validation of the HCC827-ER1 drug-resistant cell line. Source: Crown Bioscience “HCC827 NSCLC Cell Line Derived Xenograft Model”

An in vivo combination therapy confirmed c-MET amplification as the mechanism of resistance for HCC827-ER1. This cell line has been used in several published studies (here and here, for example) on mechanisms of resistance and/or new drug candidates.

FDA Approval Supported by Drug-Resistant In Vivo Models

Rybrevant is the first FDA-approved targeted treatment for patients with NSCLC with EGFR exon 20 insertion mutations. This medication provides patients with a new option to combat drug resistance, and the evidence package supporting the approval of this drug included key in vivo drug-resistant models described below.

Researchers from Janssen Research and Development tested the efficacy of the novel bispecific antibody (JNJ-61186372 [Rybrevant]) against EGFR-TKI-resistant lung tumors.

They found that the antibody effectively bound to both EGFR and c-MET (as expected), and treatment in NSCLC tumor models (including HCC827-ER1) resulted in tumor regression. However, they also reported that some NSCLC tumor models continued to grow, indicating resistance.

In a follow-up study, researchers sought to use proteomics to profile in vivo signaling changes that occur in osimertinib- and JNJ-61186372-resistant tumors from their NSCLC tumor models, including HCC827-ER1. This new approach enabled them to identify tyrosine phosphorylation rewiring as a mechanism of resistance. They noted that this finding would not have been possible using cell population averages from in vitro analyses.

Conclusion

Cancer drug resistance remains a major challenge in oncology. By leveraging drug-resistant models, such as the HCC827-ER cell line, preclinical studies can investigate new mechanisms of resistance and test new strategies and treatments, including combination or next-generation therapies.

To read Crown Bioscience’s full application note on drug-resistant HCC827, please click here. You can learn more about our CDX models here.


Related Posts