Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies

Alexander, Peter; Wang, Xiaofan

doi:10.1007/s11684-015-0396-9

Cited by 40 publications

(27 citation statements)

References 30 publications

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“…In the case of patients undergoing crizotinib therapy, acquired resistance usually occurs within one year after the first administration [24]. Although some of the bypass mechanisms that cells exploit to become resistant to RTK-targeted therapy have been described [38,39], there are still many tumors that are resistant due to unknown mechanisms. The glycosylation machinery of cancer cells is altered leading to diverse aberrant glycosylation profiles of tumor cells and constituting a potential mechanism for the observed differential efficacy of targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Effect of Increased α2,3-Sialylation on RTK Activation in MKN45 Gastric Cancer Spheroids Treated with Crizotinib

Balmaña

Diniz

Feijão

et al. 2020

IJMS

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In the scenario of personalized medicine, targeted therapies are currently the focus of cancer drug development. These drugs can block the growth and spread of tumor cells by interfering with key molecules involved in malignancy, such as receptor tyrosine kinases (RTKs). MET and Recepteur d’Origine Nantais (RON), which are RTKs frequently overactivated in gastric cancer, are glycoprotein receptors whose activation have been shown to be modulated by the cellular glycosylation. In this work, we address the role of sialylation in gastric cancer therapy using an innovative 3D high-throughput cell culture methodology that mimics better the in vivo tumor features. We evaluate the response to targeted treatment of glycoengineered gastric cancer cell models overexpressing the sialyltransferases ST3GAL4 or ST3GAL6 by subjecting 3D spheroids to the tyrosine kinase inhibitor crizotinib. We show here that 3D spheroids of ST3GAL4 or ST3GAL6 overexpressing MKN45 gastric cancer cells are less affected by the inhibitor. In addition, we disclose a potential compensatory pathway via activation of the Insulin Receptor upon crizotinib treatment. Our results suggest that cell sialylation, in addition of being involved in tumor progression, could play a critical role in the response to tyrosine kinase inhibitors in gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Analysis of the Effect of Increased α2,3-Sialylation on RTK Activation in MKN45 Gastric Cancer Spheroids Treated with Crizotinib

Balmaña

Diniz

Feijão

et al. 2020

IJMS

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“…This suggests that the PIK3CA mutation is not a sufficient oncogenic driver to confer SM1-71 resistance. Such cell line-specific differences are observed with many kinase inhibitors and arise from the specific signaling biology of the lines (36,37). However, because SM1-71 has multiple targets, we cannot fully exclude other mechanisms that might be con-tributing toward the overall sensitivity and resistance effects of the compound.…”

Section: Editors' Pick: Deciphering Cancer Signaling Vulnerabilitiesmentioning

confidence: 99%

A multitargeted probe-based strategy to identify signaling vulnerabilities in cancers

Rao

Hafner

et al. 2019

Journal of Biological Chemistry

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Edited by Eric R. FearonMost cancer cells are dependent on a network of deregulated signaling pathways for survival and are insensitive, or rapidly evolve resistance, to selective inhibitors aimed at a single target. For these reasons, drugs that target more than one protein (polypharmacology) can be clinically advantageous. The discovery of useful polypharmacology remains serendipitous and is challenging to characterize and validate. In this study, we developed a non-genetic strategy for the identification of pathways that drive cancer cell proliferation and represent exploitable signaling vulnerabilities. Our approach is based on using a multitargeted kinase inhibitor, SM1-71, as a tool compound to identify combinations of targets whose simultaneous inhibition elicits a potent cytotoxic effect. As a proof of concept, we applied this approach to a KRAS-dependent non-small cell lung cancer (NSCLC) cell line, H23-KRAS G12C . Using a combination of phenotypic screens, signaling analyses, and kinase inhibitors, we found that dual inhibition of MEK1/2 and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) is critical for blocking proliferation in cells. Our work supports the value of multitargeted tool compounds with well-validated polypharmacology and target space as tools to discover kinase dependences in cancer. We propose that the strategy described here is complementary to existing genetics-based approaches, generalizable to other systems, and enabling for future mechanistic and translational studies of polypharmacology in the context of signaling vulnerabilities in cancers.

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“…Resistance-One proposed mechanism for the development of resistance to targeted cancer therapy involves utilization of alternate signaling molecules by cancer cells to bypass pharmacological inhibition and maintain signaling output (11)(12)(13). To identify RTKs that might mediate drug resistance in HER2-positive breast cancer, we conducted an unbiased bioinformatic screen of all human RTKs by analyzing gene expression data of HER2-positive patients from an integrative database consisting of 22 publicly available data sets.…”

Section: Bioinformatic Identification and Experimental Validation Of mentioning

confidence: 99%

Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer

Alexander

Chen

Gong

et al. 2017

Journal of Biological Chemistry

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Edited by Eric R. FearonTargeted inhibitors of the human epidermal growth factor receptor 2 (HER2), such as trastuzumab and lapatinib, are among the first examples of molecularly targeted cancer therapy and have proven largely effective for the treatment of HER2-positive breast cancers. However, approximately half of those patients either do not respond to these therapies or develop secondary resistance. Although a few signaling pathways have been implicated, a comprehensive understanding of mechanisms underlying HER2 inhibitor drug resistance is still lacking. To address this critical question, we undertook a concerted approach using patient expression data sets, HER2-positive cell lines, and tumor samples biopsied both before and after trastuzumab treatment. Together, these methods revealed that high expression and activation of a specific subset of receptor tyrosine kinases (RTKs) was strongly associated with poor clinical prognosis and the development of resistance. Mechanistically, these RTKs are capable of maintaining downstream signal transduction to promote tumor growth via the suppression of cellular senescence. Consequently, these findings provide the rationale for the design of therapeutic strategies for overcoming drug resistance in breast cancer via combinational inhibition of the limited number of targets from this specific subset of RTKs.Breast cancer is the most common invasive cancer in women, accounting for more than 40,000 deaths in the United States per year (1). The HER2-positive subtype comprises ϳ20% of all breast cancers and is defined as displaying overexpression of the human epidermal growth factor receptor 2 (HER2) protein or amplification of the ERBB2 gene, as assayed by immunohistochemistry or fluorescence in situ hybridization, respectively. HER2 is a transmembrane protein that heterodimerizes with and activates other members of the ErbB family of receptor tyrosine kinases, resulting in increased cell growth and proliferation (2). In addition to breast cancer, HER2 overexpression or ERBB2 gene amplification occurs in several other human malignancies, including ovarian, stomach, and uterine cancers (3), where it is also associated with recurrence and poor prognosis (4). Targeted HER2 inhibitors, including the monoclonal antibodies trastuzumab (trade name Herceptin) and pertuzumab, the EGFR/HER2 inhibitor lapatinib, and the antibodydrug conjugate trastuzumab emtansine (T-DM1) have been the standard of care for HER2-positive breast cancer since the Food and Drug Administration approval of trastuzumab in 1998 (5).Although targeted HER2 inhibition has proven largely effective for the treatment of HER2-positive breast cancers, approximately 40 -60% of all patients either do not respond to treatment or respond initially but eventually acquire secondary resistance (6, 7). Several anticancer drug resistance mechanisms have been identified, including HER2 proteolysis, Mucin-4 overexpression, and loss of the PTEN phosphatase (8). However, these mechanisms are either not easily targetable or ar...

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Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies

Cited by 40 publications

References 30 publications

Analysis of the Effect of Increased α2,3-Sialylation on RTK Activation in MKN45 Gastric Cancer Spheroids Treated with Crizotinib

Analysis of the Effect of Increased α2,3-Sialylation on RTK Activation in MKN45 Gastric Cancer Spheroids Treated with Crizotinib

A multitargeted probe-based strategy to identify signaling vulnerabilities in cancers

Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer

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