KRAS-Mutant Lung Cancers in the Era of Targeted Therapy

Naidoo, Jarushka; Drilon, Alexander

doi:10.1007/978-3-319-24223-1_8

Cited by 26 publications

(27 citation statements)

References 68 publications

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“…Despite intense efforts to target KRAS or its key effectors, compensatory pathways have limited the ability of such agents to achieve clinical impact [26, 27]. Although KRAS drives tumorigenesis of lung and pancreatic cancer, we and others [3] find that only certain KRAS mutant lung cancers continue to need KRAS during tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers

et al. 2017

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Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein Galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvβ3, Galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance. Disrupting αvβ3/Galectin-3 binding with a clinically active drug prevents their association with mutant KRAS, thereby suppressing macropinocytosis while increasing reactive oxygen species to eradicate αvβ3-expressing KRAS mutant lung and pancreatic cancer patient-derived xenografts and spontaneous tumors in mice. Our work reveals Galectin-3 as a druggable target for KRAS-addicted lung and pancreas cancer, and indicates integrin αvβ3 as a biomarker to identify susceptible tumors.

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Section: Discussionmentioning

confidence: 99%

Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers

et al. 2017

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“…Growth factors bind to their receptors, receptor auto-phosphorylation occurs leading to activation of downstream signaling cascades such as the phosphoinositide-3-kinase (PI3K)/Protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway that results in increased survival/proliferation and inhibition of apoptosis [10,11,12,13]. Another pathway activated by GF signaling is the RAS/mitogen activated protein kinases (MAPK) pathway.…”

Section: Introductionmentioning

confidence: 99%

“…Another pathway activated by GF signaling is the RAS/mitogen activated protein kinases (MAPK) pathway. GF binding to the activated receptor through the involvement of the Grb2/SOS complex renders Ras in the GTP-bound form, activating Raf, MEK and MAPK further downstream [13,14,15,16]. Cancer cells often exhibit mutations that allow them to constitutively enhance proliferation while inhibiting apoptosis/cell death pathways.…”

Section: Introductionmentioning

confidence: 99%

Metformin in Lung Cancer: Review of in Vitro and in Vivo Animal Studies

Yousef

Tsiani

2017

Cancers

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Cancer cells display enhanced growth rates and a resistance to apoptosis. The ability of cancer cells to evade homeostasis and proliferate uncontrollably while avoiding programmed cell death/apoptosis is acquired through mutations to key signaling molecules, which regulate pathways involved in cell proliferation and survival and these mutations allow them to develop resistance to many chemotherapeutic agents, highlighting the need for development of new potent anti-cancer agents. Metformin has long been used as a treatment for type 2 diabetes and has recently attracted attention as a potential agent to be used in the treatment of cancer. The present review summarizes the existing in vitro and in vivo animal studies focusing on the anti-lung cancer effects of metformin and its effects on key proliferative and anti-apoptotic signaling pathways.

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“…It has been reported that small RhoGTPase play an important role in small cell lung cancer (Bhattacharya et al, 2015;Naidoo and Drilon, 2016). Therefore, possible use of statins or prenylation inhibitors in combination with standard therapy of non-small cell lung cancer may improve the clinical outcome of this incurable and devastating disease.…”

Section: Discussionmentioning

confidence: 99%

Could drugs inhibiting the mevalonate pathway also target cancer stem cells?

Likus

Siemianowicz

Bieńk

et al. 2016

Drug Resistance Updates

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Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell stemness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity-related cardiovascular diseases. Its prominent role in regulation of cell growth and stemness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of Abbreviations: ACAT, acetoacetyl-CoA transferase; acetyl-CoA, acetyl-coenzyme A; Arp2/3, actin-related protein 2/3 (actin polymerizing complex) BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4. 0/). 14 W. Likus et al. / Drug Resistance Updates 25 (2016) 13-25 the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly highlight diverse functions of various elements of this mevalonate pathway. We further discuss in detail the role of elements of the mevalonate cascade in stemness, carcinogenesis, cancer progression, metastasis and maintenance of cancer stem cells.

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KRAS-Mutant Lung Cancers in the Era of Targeted Therapy

Cited by 26 publications

References 68 publications

Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers

Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers

Metformin in Lung Cancer: Review of in Vitro and in Vivo Animal Studies

Could drugs inhibiting the mevalonate pathway also target cancer stem cells?

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