Clinical utility of PDX cohorts to reveal biomarkers of intrinsic resistance and clonal architecture changes underlying acquired resistance to cetuximab in HNSCC

Abstract

Cetuximab is a widely used drug for treating head and neck squamous cell carcinomas (HNSCCs); however, it provides restricted clinical benefits, and its response duration is limited by drug resistance. Here, we conducted randomized “Phase II-like clinical trials” of 49 HNSCC PDX models and reveal multiple informative biomarkers for intrinsic resistance to cetuximab (e.g., amplification of ANKH, up-regulation of PARP3). After validating these intrinsic resistance biomarkers in another HNSCC PDX cohort (61 PDX models), we generated acquired cetuximab resistance PDX models and analyzed them to uncover resistance mechanisms. Whole exome sequencing and transcriptome sequencing revealed diverse patterns of clonal selection in acquired resistant PDXs, including the emergence of subclones with strongly activated RAS/MAPK. Extending these insights, we show that a combination of a RAC1/RAC3 dual-target inhibitor and cetuximab could overcome acquired cetuximab resistance in vitro and in vivo. Beyond revealing intrinsic resistance biomarkers, our PDX-based study shows how clonal architecture changes underlying acquired resistance can be targeted to expand the therapeutic utility of this important drug to more HNSCC patients.

A biomimetic nanoplatform for customized photothermal therapy of HNSCC evaluated on patient-derived xenograft models

“…PDX models were established according to our previous report. 61 Briefly, each fresh tumor fragment from an HNSCC patient numbered SCC2676 was subcutaneously engrafted into BALB/c nude mice. After vigorous tumor growth, the mice were tested with further treatment.…”

Pharmacogenomic landscape of head and neck squamous cell carcinoma informs precision oncology therapy

“…Although we show here that this PDC resource is useful for screening drugs that directly inhibit tumor cell proliferation, the lack of a functional immune system in the model represents a major limitation that prevents their application for studying cancer immunology and for preclinical screening of immunomodulatory therapeutics ( 40 , 86 ). There are efforts underway to overcome this limitation.…”

“…All animal experimental procedures were approved by the Institutional Animal Care and Use Committee of the Ninth People’s Hospital of the Shanghai JiaoTong University School of Medicine. We previously reported the methods of generation PDX models with HNSCC tissues ( 40 ). Briefly, small fragments (50 mm 3 ) of the tumor samples were subcutaneously engrafted into the scapular area of anesthetized immunodeficient athymic BALB/c-nu/nu mouse [4 weeks old, female, Shanghai Laboratory Animal Research Center (SLARC)], and tumor volumes were determined at least once a week.…”

“…Moreover, clinical evidence has demonstrated the improved treatment response rates using pharmacotyping of PDCs to identify patients who are sensitive to guide therapeutic decisions in solid tumors and hematological malignancies ( 29 , 38 , 39 ). The low drug-response rates of treatments currently used in HNSCCs may reflect the extensive inter- and intratumoral heterogeneity known to occur in HNSCCs ( 3 , 40 ), which presents a major obstacle in the precise treatment of HNSCCs.…”

Identifying CDC7 as a synergistic target of chemotherapy in resistant small-cell lung cancer via CRISPR/Cas9 screening

“…Preclinical models are effective tools for assessing the efficacy of novel antitumor strategies before clinical trials. In particular, PDXs have been shown to be useful in evaluating the tolerability and efficacy of new agents and treatment strategies prior to patient trials [ 22 , 23 ]. However, acquiring SCLC tissues is difficult owing to the short surgery window for SCLC, and efficacy assessments using a PDX model are time-consuming.…”