MET activation confers resistance to cetuximab, and prevents HER2 and HER3 upregulation in head and neck cancer

Novoplansky, Ofra; Fury, Matthew G.; Prasad, Manu; Yegodayev, Ksenia M.; Zorea, Jonathan; Cohen, Limor; Pelossof, Raphael; Cohen, Liz; Katabi, Nora; Cecchi, Fabiola; Joshua, Ben‐Zion; Popovtzer, Aron; Baselga, José; Scaltriti, Maurizio; Elkabets, Moshe

doi:10.1002/ijc.32170

Cited by 23 publications

(25 citation statements)

References 67 publications

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“…Using CAFs isolated from Cetuximab Prog -PDX we were able to demonstrate that in addition to enhancing HNC cell proliferation, CAFs reduce sensitivity to cetuximab both in vitro and in vivo ( Figures 3C and 4A). We speculate that the mechanism by which CAFs interfere with cetuximab treatment involves the secretion of HGF, which was previously reported to be a mechanism of resistance [21,35,58]. However, the role of TGF-beta-activated CAFs in HGF secretion as a mechanism of resistance to cetuximab calls for further investigation.…”

Section: Discussionmentioning

confidence: 77%

“…Unfortunately, the vast majority of patients experience recurrent or progressive disease [4,12]. The resistance to cetuximab can come in different forms, either by cell-autonomous resistance mechanisms (e.g., gene mutations, receptors upregulation, and feedback loops) or by the cells in the TME, which provide an extrinsic resistance mechanism (for example, secretion of growth factors) ( [21,35,40,41] and reviewed in [42]).…”

Section: Discussionmentioning

confidence: 99%

“…To study the effect of TGF-beta-activated CAFs on HNC cell line growth in vivo, the cetuximab-sensitive cell line CAL33 [35,36] was injected subcutaneously into NOD/SCID mice, with or without TGF-beta-activated CAFs. CAFs promoted tumor growth in a ratio-dependent manner, compared with CAL33 alone, indicated by tumor volume ( Figure S4A).…”

Section: Tgf-beta-activated Cafs Reduce Sensitivity To Cetuximab In Vmentioning

confidence: 99%

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TGF-Beta-Activated Cancer-Associated Fibroblasts Limit Cetuximab Efficacy in Preclinical Models of Head and Neck Cancer

Yegodayev

Novoplansky

Golden

et al. 2020

Cancers

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Most head and neck cancer (HNC) patients are resistant to cetuximab, an antibody against the epidermal growth factor receptor. Such therapy resistance is known to be mediated, in part, by stromal cells surrounding the tumor cells; however, the mechanisms underlying such a resistance phenotype remain unclear. To identify the mechanisms of cetuximab resistance in an unbiased manner, RNA-sequencing (RNA-seq) of HNC patient-derived xenografts (PDXs) was performed. Comparing the gene expression of HNC-PDXs before and after treatment with cetuximab indicated that the transforming growth factor-beta (TGF-beta) signaling pathway was upregulated in the stromal cells of PDXs that progressed on cetuximab treatment (CetuximabProg-PDX). However, in PDXs that were extremely sensitive to cetuximab (CetuximabSen-PDX), the TGF-beta pathway was downregulated in the stromal compartment. Histopathological analysis of PDXs showed that TGF-beta-activation was detected in cancer-associated fibroblasts (CAFs) of CetuximabProg-PDX. These TGF-beta-activated CAFs were sufficient to limit cetuximab efficacy in vitro and in vivo. Moreover, blocking the TGF-beta pathway using the SMAD3 inhibitor, SIS3, enhanced cetuximab efficacy and prevented the progression of CetuximabProg-PDX. Altogether, our findings indicate that TGF-beta-activated CAFs play a role in limiting cetuximab efficacy in HNC.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Tgf-beta-activated Cafs Reduce Sensitivity To Cetuximab In Vmentioning

confidence: 99%

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TGF-Beta-Activated Cancer-Associated Fibroblasts Limit Cetuximab Efficacy in Preclinical Models of Head and Neck Cancer

Yegodayev

Novoplansky

Golden

et al. 2020

Cancers

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“…44 Unlike in colorectal and lung cancers, the treatment regimen for HNSCC patients is not determined on the basis of molecular determinants of responses. 45 In the present study, we explored the molecular mechanism of resistance to cetuximab in HNSCC. In our present study, with the increase of cetuximab concentration and treatment time, the SPP1 overexpression group showed significant drug resistance, while the SPP1 knockdown group showed significant treatment efficacy.…”

Section: Spp1 Accelerates Malignant Biological Behaviors In Vitro Amentioning

confidence: 99%

Upregulation of secreted phosphoprotein 1 affects malignant progression, prognosis, and resistance to cetuximab via the KRAS/MEK pathway in head and neck cancer

Jiang

et al. 2020

Molecular Carcinogenesis

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Acquired resistance is a barrier to cetuximab efficacy in patients with head and neck squamous cell carcinoma (HNSCC). Secreted phosphoprotein 1 (SPP1) is involved in various biological processes, including immune responses, cancer progression, and prognosis in many cancers, while little is known in HNSCC. Bioinformatics methods were used to identify candidate genes and further in vivo and in vitro experiments were performed to examine and validate the function of SPP1. We found that SPP1 was upregulated and has been found to have an oncogenic role in HNSCC. We further confirmed that overexpression of SPP1 affected proliferation, migration, invasion, and survival, and inhibited apoptosis, whereas silencing of SPP1 yielded opposite results to those of SPP1 overexpression. In addition, activation of the KRAS/MEK pathway contributed to the SPP1‐induced malignant progression of HNSCC and resistance to cetuximab. Furthermore, SPP1 knockdown or an MEK inhibitor overcame this cetuximab‐resistance pattern. Taken together, our findings for the first time identify the role of SPP1 in tumor promotion, prognostic prediction, and potential therapeutic targeting, as well as resistance to cetuximab in HNSCC.

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“…In addition to HER-directed antibodies, Dr. Mendelsohn's work also catalyzed the development of other modalities to target HERs, including TKIs such as Iressa and subsequent generations of TKIs with distinct model of actions (72). The concept of blocking therapeutic antibodies has also been applied to other upregulated RTKs, such as MET and IGF1R receptors, which have been shown to confer therapeutic resistance and are also excellent targets for combination EGFR therapies (73)(74)(75)(76)(77). Further, therapeutic resistance to HERs antibodies or TKI might involve nonreceptor kinases such as SRC (78) as well as other pathways in a cell-type context-dependent manner.…”

Section: Blocking Therapeutic Egfr Monoclonal Antibodies From Bench Tmentioning

confidence: 99%

A Tribute to John Mendelsohn: A Pioneer in Targeted Cancer Therapy

et al. 2019

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Cancer scientists and clinicians are mourning the death of one of the most accomplished members of their community: Dr. John Mendelsohn. He was a pioneer in targeted cancer therapy and was instrumental for the discovery and deployment of the first antagonist epidermal growth factor receptor (EGFR) therapeutic antibodies, broadening the concept of targeted EGFR therapy to encompass other receptor tyrosine kinases, such as HER2, and developing blocking antibodycombination therapy with chemotherapies or radiotherapy. Dr. Mendelsohn, who died on January 7, 2019, always led by the strength of his accomplishments and the humility of his character. Above all, he was a well-revered mentor and clini-cian, who extended compassion and the gift of his time to patients, colleagues, and mentees alike. In tribute to Dr. Mendelsohn, Cancer Research has invited his former mentees and colleagues who were associated with Dr. Mendelsohn for over three decades to reflect on the broad impact of his work. Here, we discuss Dr. Mendelsohn's illustrious career at three elite academic cancer institutions and hospitals in the United States, his acumen to build, grow, and uplift institutions, and train a generation of medical oncologists, physician scientists, and cancer biologists. His profound legacy on targeted therapy and cancer research and treatment continue to prolong and save the lives of cancer patients globally.

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MET activation confers resistance to cetuximab, and prevents HER2 and HER3 upregulation in head and neck cancer

Cited by 23 publications

References 67 publications

TGF-Beta-Activated Cancer-Associated Fibroblasts Limit Cetuximab Efficacy in Preclinical Models of Head and Neck Cancer

TGF-Beta-Activated Cancer-Associated Fibroblasts Limit Cetuximab Efficacy in Preclinical Models of Head and Neck Cancer

Upregulation of secreted phosphoprotein 1 affects malignant progression, prognosis, and resistance to cetuximab via the KRAS/MEK pathway in head and neck cancer

A Tribute to John Mendelsohn: A Pioneer in Targeted Cancer Therapy

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