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Updates on the Molecular Profile of Gastrointestinal Stromal Tumors (Volume...
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Updates on the Molecular Profile of Gastrointestinal Stromal Tumors (Volume II)

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: 31 October 2024 | Viewed by 2658

Special Issue Editors

Dr. Maria Cristina Sini

E-Mail Website
Guest Editor
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche (CNR), 07100 Sassari, Italy
Interests: molecular profile of gastrointestinal stromal tumors (GIST); clinical cancer genomic profiling; translational medicine; molecular genetics; cancer; solid tumor; molecular biomarkers; NGS technologies
Special Issues, Collections and Topics in MDPI journals
Dr. Grazia Palomba

E-Mail Website
Guest Editor
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche (CNR), 07100 Sassari, Italy
Interests: molecular profile of gastrointestinal stromal tumors (GIST); clinical cancer genomic profiling; translational medicine; molecular genetics; cancer; solid tumor; molecular biomarkers; NGS technologies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second edition of "Updates on the Molecular Profile of Gastrointestinal Stromal Tumors" (https://www.mdpi.com/journal/cancers/special_issues/Molecular_Profile_GIST).

Gastrointestinal stromal tumors (GIST), although relatively rare, are the most common primary mesenchymal tumors of the gastrointestinal tract. Most GISTs tumors harbor activating mutations in the tyrosine kinase receptor c-KIT and express the tyrosine kinase KIT oncoprotein. Another member of the RTK family, PDGFRα, is associated with the pathogenesis of GIST.

Tumor stage classification and the molecular profile are important for tumor diagnosis and indispensable for individualized treatment against malignancies. Genotyping has become an integral part of the management of GISTs undergoing tyrosine kinase inhibitor therapy.

In this Special Issue, we focus on novel tumor biomarkers to investigate immunological profiles in gastrointestinal stromal tumors. Immune microenvironment profiling of gastrointestinal stromal tumors (GIST) could define novel gene expression patterns associated with immune checkpoint inhibitor responses.

This Special Issue aims to collect original research, short communications, or timely reviews on clinical, pathological, and molecular aspects and alternative approaches for the treatment of GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies.

Dr. Maria Cristina Sini
Dr. Grazia Palomba
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • molecular profile
  • novel tumor biomarkers
  • predictive biomarkers for therapeutic outcomes
  • immunological profile
  • GIST immune microenvironment
  • immunotherapy

Published Papers (2 papers)

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Research

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26 pages, 6313 KiB  
Article
Unraveling the Mechanisms of Sensitivity to Anti-FGF Therapies in Imatinib-Resistant Gastrointestinal Stromal Tumors (GIST) Lacking Secondary KIT Mutations
by Sergei Boichuk, Pavel Dunaev, Vera Skripova, Aigul Galembikova, Firyuza Bikinieva, Elena Shagimardanova, Guzel Gazizova, Ruslan Deviatiiarov, Elena Valeeva, Ekaterina Mikheeva, Maria Vasilyeva, Pavel Kopnin, Vladimir Strelnikov and Ramziya Kiyamova
Cancers 2023, 15(22), 5354; https://doi.org/10.3390/cancers15225354 - 09 Nov 2023
Viewed by 1100
Abstract
We showed previously that inhibition of KIT signaling in GISTs activates FGFR-signaling pathway rendering cancer cells resistant to receptor tyrosine kinase inhibitor (RTKi) imatinib mesylate (IM) (Gleevec) despite of absence of secondary KIT mutations and thereby illustrating a rationale for the combined (e.g., [...] Read more.
We showed previously that inhibition of KIT signaling in GISTs activates FGFR-signaling pathway rendering cancer cells resistant to receptor tyrosine kinase inhibitor (RTKi) imatinib mesylate (IM) (Gleevec) despite of absence of secondary KIT mutations and thereby illustrating a rationale for the combined (e.g., KIT- and FGFR-targeted) therapies. We show here that long-term culture of IM-resistant GISTs (GIST-R1) with IM substantially down-regulates KIT expression and induces activation of the FGFR-signaling cascade, evidenced by increased expression of total and phosphorylated forms of FGFR1 and 2, FGF-2, and FRS-2, the well-known adaptor protein of the FGF-signaling cascade. This resulted in activation of both AKT- and MAPK-signaling pathways shown on mRNA and protein levels, and rendered cancer cells highly sensitive to pan-FGFR-inhibitors (BGJ 398, AZD 4547, and TAS-120). Indeed, we observed a significant decrease of IC50 values for BGJ 398 in the GIST subclone (GIST-R2) derived from GIST-R1 cells continuously treated with IM for up to 12 months. An increased sensitivity of GIST-R2 cells to FGFR inhibition was also revealed on the xenograft models, illustrating a substantial (>70%) decrease in tumor size in BGJ 398-treated animals when treated with this pan-FGFR inhibitor. Similarly, an increased intra-tumoral apoptosis as detected by immunohistochemical (IHC)-staining for cleaved caspase-3 on day 5 of the treatment was found. As expected, both BGJ 398 and IM used alone lacked the pro-apoptotic and growth-inhibitory activities on GIST-R1 xenografts, thereby revealing their resistance to these TKis when used alone. Important, the knockdown of FGFR2, and, in much less content, FGF-2, abrogated BGJ 398′s activity against GIST-R2 cells both in vitro and in vivo, thereby illustrating the FGF-2/FGFR2-signaling axis in IM-resistant GISTs as a primary molecular target for this RTKi. Collectively, our data illustrates that continuous inhibition of KIT signaling in IM-resistant GISTs lacking secondary KIT mutations induced clonal heterogeneity of GISTs and resulted in accumulation of cancer cells with overexpressed FGF-2 and FGFR1/2, thereby leading to activation of FGFR-signaling. This in turn rendered these cells extremely sensitive to the pan-FGFR inhibitors used in combination with IM, or even alone, and suggests a rationale to re-evaluate the effectiveness of FGFR-inhibitors in order to improve the second-line therapeutic strategies for selected subgroups of GIST patients (e.g., IM-resistant GISTs lacking secondary KIT mutations and exhibiting the activation of the FGFR-signaling pathway). Full article
(This article belongs to the Special Issue Updates on the Molecular Profile of Gastrointestinal Stromal Tumors (Volume II))
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Review

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15 pages, 311 KiB  
Review
KIT and PDGFRA Variants and the Survival of Patients with Gastrointestinal Stromal Tumor Treated with Adjuvant Imatinib
by Heikki Joensuu
Cancers 2023, 15(15), 3879; https://doi.org/10.3390/cancers15153879 - 30 Jul 2023
Cited by 2 | Viewed by 1269
Abstract
Adjuvant imatinib improves the recurrence-free survival and overall survival (OS) of patients with gastrointestinal stromal tumors (GISTs) who have a high risk of recurrence after surgery and is now considered standard treatment. Yet, OS benefit has been demonstrated in only one randomized study, [...] Read more.
Adjuvant imatinib improves the recurrence-free survival and overall survival (OS) of patients with gastrointestinal stromal tumors (GISTs) who have a high risk of recurrence after surgery and is now considered standard treatment. Yet, OS benefit has been demonstrated in only one randomized study, the Scandinavian Sarcoma Group XVIII/AIO trial, where patients with high-risk GISTs were allocated to either 1 year or 3 years of adjuvant imatinib. SSGXVIII/AIO is also the only randomized trial in which adjuvant imatinib duration exceeding 2 years was evaluated. In this trial, the 3-year treatment led to a 45% reduction in the risk of death during the first 10 years that followed random allocation even though some of the patients did not have GISTs at tumor histology review, had mutations now known to be imatinib-resistant or had non-localized disease at study entry. In the subgroup of patients who had KIT exon 11 deletion/indel mutation, the reduction in the risk of death was 66% in favor of the longer treatment. Proper patient selection is of crucial importance since many patients are cured with surgery. Little evidence for OS benefit is available from randomized trials for patients whose GIST harbors KIT exon 9 mutation, KIT insertion mutation, PDGFRA D842V mutation, or lacks KIT and PDGFRA mutations. Adjuvant imatinib improves OS substantially if high-risk GISTs can be identified, treatment duration is long enough, and GISTs harbor an imatinib-sensitive mutation. Full article
(This article belongs to the Special Issue Updates on the Molecular Profile of Gastrointestinal Stromal Tumors (Volume II))
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