Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance

Miller, Miles A.; Oudin, Madeleine J.; Sullivan, Ryan J.; Wang, Stephanie J.; Meyer, Aaron S.; Im, Hyungsoon; Frederick, Dennie T.; Tadros, Jenny; Griffith, Linda G.; Lee, Hakho; Weissleder, Ralph; Flaherty, Keith T.; Gertler, Frank B.; Lauffenburger, Douglas A.

doi:10.1158/2159-8290.cd-15-0933

Cited by 148 publications

(173 citation statements)

References 59 publications

Supporting

Mentioning

165

Contrasting

Unclassified

Order By: Relevance

“…Strong experimental evidence supports the consensus that TAM receptors, in a cell-autonomous manner, act as pro-oncogenes enhancing the growth, survival, migration, and epithelial-to-mesenchymal transition of tumor cells [19]. TAM receptors have also been implicated in boosting metastasis and resistance to chemotherapeutic agents [20,21,22,23], two of the most therapeutically challenging hallmarks of cancer. Notably, targeted inhibition of TAM signaling has proven to have robust anti-tumor efficacy in diverse experimental cancer settings.…”

Section: Introductionmentioning

confidence: 93%

“…Similarly, TAM ligands can form dimers [41]. Shedding of the extracellular domain upon receptor activation has been described, in particular for Axl and Mer [42,43], and is believed to be of physiological relevance, for instance, to acquire resistance to chemotherapy [23] or as decoy soluble receptors [44]. Similar to several proteins of the coagulation cascades, TAM ligands possess a gamma-carboxyglutamic acid-rich (Gla) domain [36].…”

Section: Tam Receptors and Ligands: A Brief Overviewmentioning

confidence: 99%

See 1 more Smart Citation

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

Paolino

Penninger

2016

Cancers

View full text Add to dashboard Cite

The TAM receptor protein tyrosine kinases—Tyro3, Axl, and Mer—are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. Importantly, TAM receptors have also been associated with cancer development and progression. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of diverse immune cells. Thus, modulation of TAM receptors has emerged as a potential novel strategy for cancer treatment. In this review, we discuss our current understanding of how TAM receptors control immunity, with a particular focus on the regulation of anti-tumor responses and its implications for cancer immunotherapy.

show abstract

Section: Introductionmentioning

confidence: 93%

Section: Tam Receptors and Ligands: A Brief Overviewmentioning

confidence: 99%

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

Paolino

Penninger

2016

Cancers

View full text Add to dashboard Cite

show abstract

“…In human colorectal cancer (CRC), ADAM overexpression is often correlated with CRC progression, invasiveness and poor clinical outcome [103, 104]. Furthermore, in human breast cancers, ADAM10 and ADAM17 have been implicated in conferring resistance to specific cancer therapies including HER2/ErbB resistance[105–108]. While detailed understanding of the role of ADAM10 in human CRC is still limited, recent insights into the importance of ADAM10 signaling in CRC initiation and progression have been made using experimental mouse tumor models.…”

Section: Adam10 and Intestinal Tumorigenesismentioning

confidence: 99%

Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

Dempsey

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

View full text Add to dashboard Cite

A disintegrin and metalloproteinases (ADAMs) are a family of multidomain, membrane-anchored proteases that regulate diverse cellular functions, including cell adhesion, migration, proteolysis and other cell signaling events. Catalytically-active ADAMs act as ectodomain sheddases that proteolytically cleave type I and type II transmembrane proteins and some GPI-anchored proteins from the cellular surface. ADAMs can also modulate other cellular signaling events through a process known as regulated intramembrane proteolysis (RIP). Through their proteolytic activity, ADAMs can rapidly modulate key cell signaling pathways in response to changes in the extracellular environment (e.g. inflammation) and play a central role in coordinating intercellular communication. Dysregulation of these processes through aberrant expression, or sustained ADAM activity, is linked to chronic inflammation, inflammation-associated cancer and tumorigenesis. ADAM10 was the first disintegrin-metalloproteinase demonstrated to have proteolytic activity and is the prototypic ADAM associated with RIP activity (e.g. sequential Notch receptor processing). ADAM10 is abundantly expressed throughout the gastrointestinal tract and during normal intestinal homeostasis ADAM10 regulates many cellular processes associated with intestinal development, cell fate specification and maintenance of intestinal stem cell/progenitor populations. In addition, several signaling pathways that undergo ectodomain shedding by ADAM10 (e.g. Notch, EGFR/ErbB, IL-6/sIL-6R) help control intestinal injury/regenerative responses and may drive intestinal inflammation and colon cancer initiation and progression. Here, I review some of the proposed functions of ADAM10 associated with intestinal crypt homeostasis and tumorigenesis within the gastrointestinal tract in vivo.

show abstract

“…Inhibition of this adaptive response by lapatinib prevents downstream Src, FAK, and Akt signaling 3 . Mechanistically, kinase inhibitor treatment can decrease shedding of RTKs, thus enhancing bypass signaling 4 . Drug treatment can also cause changes in the cell cycle, promoting resistance in the quiescent cells adapting to the treatment 5 .…”

Section: Introductionmentioning

confidence: 99%

A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance

Schwartz

Barney

Jansen

et al. 2017

Integrative Biology

Self Cite

View full text Add to dashboard Cite

Traditional drug screening methods lack features of the tumor microenvironment that contribute to resistance. Most studies examine cell response in a single biomaterial platform in depth, leaving a gap in understanding how extracellular signals such as stiffness, dimensionality, and cell-cell contacts act independently or are integrated within a cell to affect either drug sensitivity or resistance. This is critically important, as adaptive resistance is mediated, at least in part, by the extracellular matrix (ECM) of the tumor microenvironment. We developed an approach to screen drug responses in cells cultured on 2D and in 3D biomaterial environments to explore how key features of ECM mediate drug response. This approach uncovered that cells on 2D hydrogels and spheroids encapsulated in 3D hydrogels were less responsive to receptor tyrosine kinase (RTK)-targeting drugs sorafenib and lapatinib, but not cytotoxic drugs, compared to single cells in hydrogels and cells on plastic. We found that transcriptomic differences between these in vitro models and tumor xenografts did not reveal mechanisms of ECM-mediated resistance to sorafenib. However, a systems biology analysis of phospho-kinome data uncovered that variation in MEK phosphorylation was associated with RTK-targeted drug resistance. Using sorafenib as a model drug, we found that co-administration with a MEK inhibitor decreased ECM-mediated resistance in vitro and reduced in vivo tumor burden compared to sorafenib alone. In sum, we provide a novel strategy for identifying and overcoming ECM-mediated resistance mechanisms by performing drug screening, phospho-kinome analysis, and systems biology across multiple biomaterial environments.

show abstract

Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance

Cited by 148 publications

References 59 publications

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance

Contact Info

Product

Resources

About