Demo

webinar

Drug-Resistant Tumor Models for Preclinical Cancer Drug Development

About the Webinar:

Drug resistance is where promising oncology programs meet clinical reality. In this webinar, Jessie Wong, Head of Cancer Pharmacology at Crown Bioscience, walks through three ways to build preclinical models that reflect how resistance develops in patients. The first uses PDX and organoid models derived from clinically pretreated or relapsed tumors, including samples from patients treated with ADCs, KRAS G12C inhibitors, PARP inhibitors, TKIs, chemotherapy, and immunotherapy.

The second induces resistance through sustained drug pressure in vivo and in vitro. The third uses CRISPR-engineered cell lines and CDX models that carry clinically observed resistance mutations for faster, higher-throughput screening.

The case studies show what these models can uncover. Paired PDX and organoid models from a breast cancer patient who progressed on sacituzumab govitecan (Trodelvy) traced resistance to payload insensitivity, and an ADC with a different payload restored tumor inhibition in vivo. Other examples cover acquired mutations in a KRAS G12C-mutant colorectal tumor, loss of surface HER2 after sustained trastuzumab deruxtecan exposure, and BRCA1 re-expression driving PARP inhibitor relapse in ovarian cancer. For teams choosing models for an ADC, targeted therapy, or IO program, it's a practical guide to matching the resistance model to the development question. Crown Bioscience is available through Science Exchange, so research teams can scope and start preclinical oncology studies under a single agreement.

Frequently Asked Questions

What is a drug-resistant PDX model?
A drug-resistant patient-derived xenograft (PDX) model is a tumor model created by implanting tumor tissue from a patient whose cancer stopped responding to treatment into immunodeficient mice. Because PDX models largely preserve the patient tumor's histopathology, molecular profile, and treatment response, they help researchers test whether new drugs can overcome clinically relevant resistance.
How are drug-resistant tumor models developed?
Crown Bioscience uses three methods. Clinically pretreated models are built from tumors collected after patients progressed or relapsed on therapy. Drug-induced models are generated by applying sustained drug pressure in vivo or in vitro until tumors relapse. Engineered models use CRISPR to introduce known resistance mutations into cell lines and CDX models for faster screening.
How can PDX models help explain ADC resistance?
Paired PDX and organoid models can separate target-related resistance from payload-related resistance. In one case, tumors from a breast cancer patient who progressed on sacituzumab govitecan still showed high Trop-2 expression but responded poorly to topoisomerase I inhibitor payloads. ADCs using a different payload class restored strong tumor inhibition, pointing to payload insensitivity as the resistance driver.
What causes resistance to KRAS G12C inhibitors?
Secondary KRAS mutations are one documented cause. In Crown Bioscience's engineered models, the Y96 mutation drove resistance to both sotorasib and adagrasib, while the H95 mutation drove resistance to adagrasib only. A pan-RAS inhibitor overcame resistance from both mutations, and CDX tumors mirrored the response patterns seen in cell-based assays.
What is the difference between PDX, PDO, and CDX models?
PDX models grow patient tumor tissue directly in mice and retain much of the original tumor's biology. Patient-derived organoids (PDOs) are 3D in vitro cultures from patient tumors, useful for faster screening. Cell line-derived xenograft (CDX) models grow established cancer cell lines in mice. Paired PDX and organoid systems let teams screen in vitro and confirm in vivo.
How does PARP inhibitor resistance develop in BRCA-mutant tumors?
One mechanism is restoration of BRCA function. In a BRCA1-mutant ovarian cancer PDX model, tumors responded well to a PARP inhibitor, then relapsed after three to four months of treatment. Analysis of the resistant tumor showed the mutation that silenced BRCA1 had been lost, allowing BRCA1 to be expressed again and restoring the DNA repair pathway PARP inhibitors exploit.
How can I access Crown Bioscience's preclinical oncology models?
Research teams can work with Crown Bioscience through Science Exchange, which connects life sciences organizations with thousands of pre-qualified partners under a single agreement. That lets you scope PDX, organoid, CDX, and resistance model studies with Crown without negotiating a separate contract.