Posts Tagged ‘cancer drug resistance’

Resistance to Receptor of Tyrosine Kinase

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Two just published articles in Science Translational Medicine report

(1) the discovery of bypass mechanisms of resistance to the receptor of tyrosine kinase inhibition (rTKI) in lung cancer
(2) receptor signaling networks in predicting drug response

Bypass Mechanisms of Resistance to Receptor Tyrosine Kinase Inhibition in Lung Cancer

Matthew J. Niederst1,2 and Jeffrey A. Engelman1,2*
1 Massachusetts General Hospital Cancer Center, Charlestown, MA
2 Department of Medicine, Harvard Medical School, Boston, MA
Sci. Signal., 24 Sep 2013; 6(294), p. re6

Abstract: Receptor tyrosine kinases (RTKs) are activated by somatic genetic alterations in a subset of cancers, and

  • such cancers are often sensitive to specific inhibitors of the activated kinase.

Two well-established examples of this paradigm include

  • lung cancers with either EGFR mutations or
  • ALK translocations.

In these cancers, inhibition of the corresponding RTK

  • leads to suppression of key downstream signaling pathways, such as
    • the PI3K (phosphatidylinositol 3-kinase)/AKT and
    • MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal–regulated kinase) pathways,

resulting in cell growth arrest and death.

Despite the initial clinical efficacy of ALK (anaplastic lymphoma kinase) and EGFR (epidermal growth factor receptor) inhibitors in these cancers,

  • resistance invariably develops, typically within 1 to 2 years.

Over the past several years, multiple molecular mechanisms of resistance have been identified, and some common themes have emerged. These are

  1. the development of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective RTK.
  2. activation of alternative RTKs that maintain the signaling of key downstream pathways
    • despite sustained inhibition of the original drug target.

Indeed, several different RTKs have been implicated in promoting resistance to EGFR and ALK inhibitors in both laboratory studies and patient samples.

In this mini-review, we summarize

  1. the concepts underlying RTK-mediated resistance,
  2. the specific examples known to date, and
  3. the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.

* Corresponding author. E-mail:

Citation: M. J. Niederst, J. A. Engelman, Bypass Mechanisms of Resistance to Receptor Tyrosine Kinase Inhibition in Lung Cancer. Sci. Signal. 6, re6 (2013).

Profiles of Basal and Stimulated Receptor Signaling Networks Predict Drug Response in Breast Cancer Lines

Mario Niepel1*{dagger}, Marc Hafner1{dagger}, Emily A. Pace2{dagger}, Mirra Chung1, Diana H. Chai2, Lili Zhou1, Birgit Schoeberl2, and Peter K. Sorger1*
1 Harvard Medical School Library of Integrated Network-based Cellular Signatures Center, Department of Systems Biology, Harvard Medical School, Boston, MA
2 Merrimack Pharmaceuticals, Cambridge, MA
Sci. Signal., 24 Sep 2013; 6(294), p. ra84
Abstract: Identifying factors responsible for variation in drug response is essential for the effective use of targeted therapeutics. We profiled signaling pathway activity in a collection of breast cancer cell lines
  • before and after stimulation with physiologically relevant ligands, which
  • revealed the variability in network activity among cells of known genotype and molecular subtype.
Despite the receptor-based classification of breast cancer subtypes, we found that
  • the abundance and activity of signaling proteins in unstimulated cells (basal profile), as well as
  • the activity of proteins in stimulated cells (signaling profile),
varied within each subtype.
Using a partial least-squares regression approach, we constructed models that significantly predicted sensitivity to 23 targeted therapeutics. For example,
  • one model showed that the response to the growth factor receptor ligand heregulin effectively predicted
    • the sensitivity of cells to drugs targeting the cell survival pathway mediated by PI3K (phosphoinositide 3-kinase) and Akt, whereas
    • the abundance of Akt or the mutational status of the enzymes in the pathway did not.
Thus, basal and signaling protein profiles may yield new biomarkers of drug sensitivity and enable the identification of appropriate therapies in cancers characterized by similar functional dysregulation of signaling networks.
* Corresponding author. E-mail: (P.K.S.); (M.N.)
Citation: M. Niepel, M. Hafner, E. A. Pace, M. Chung, D. H. Chai, L. Zhou, B. Schoeberl, P. K. Sorger, Profiles of Basal and Stimulated Receptor Signaling Networks Predict Drug Response in Breast Cancer Lines. Sci. Signal. 6, ra84 (2013).

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Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells(1)

Authors: Dejuan Kong, Aamir Ahmad, Bin Bao, Yiwei Li, Sanjeev Banarjee, Fazlul H. Sarkar, Wayne State University School of Medicine

Reporter-Curator: Stephen J. Williams, Ph.D.

Clinically, there has not been much success in treating solid tumors with histone deacetylase inhibitors (HDACi). Histone acetylation and deacetylation play an important role in transcriptional regulation of genes and increased activity is associated with many cancers, therefore it was thought that HDAC inhibition might be fruitful as a therapy.  There have been several phase I and II clinical trials using HDACi for treatment of various malignancies, including hematological and solid malignancies(2), with most success seen in hematologic malignancies such as cutaneous T-cell lymphoma and peripheral T-cell lymphoma and little or no positive outcome with solid tumors.  Many mechanisms of resistance to HDACi in solid tumors have been described, most of which are seen with other chemotherapeutics such as increased multidrug resistance gene MDR1, increased anti-apoptotic proteins and activation of cell survival pathways(3).

A report in PLOS One by Dr. Dejuan Kong, Dr. Fazlul Sarkar, and colleagues from Wayne State University School of Medicine, demonstrate another possible mechanism of resistance to HDACi in prostate cancer, by induction of the epithelial-to-mesenchymal transition (EMT), which has been associated with the development of resistance to chemotherapies in other malignancies of epithelial origin(4,5).

EMT is an important differentiation process in embryogenesis and felt to be important in progression of cancer.  Epithelial cells will acquire a mesenchymal morphology (on plastic this looks like a cuboidal epithelial cell gaining a more flattened, elongated, tri-corner morphology; see paper Figure 1) and down-regulate epithelial markers such as cytokeratin, up-regulation of mesenchymal markers, increased migration and invasiveness in standard assays, and increased resistance to chemotherapeutics, and similarity to cancer stem cells(6-10).

ImageFigure 1. HDACis led to the induction of EMT phemotype. (A and B) PC3 cells treated with TSA and SAHA for 24 h at indicated doses.  The photomicrographs of PC3 cells treated with TSA and SAHA exhibited a fibroblastic-type phenotype, while cells treated with DMAO control displayed rounded epithelial cell morphology (original magnification, x 100). (C) Treated PC3 cells show increased mesenchymal markers vimentin and ZEB1 and F-actin reorganization.  Figure taken from Kong, D., Ahmad, A., Bao, B., Li, Y., Banerjee, S., and Sarkar, F. H. (2012) PloS one 7, e45045

In this study the authors found that treatment of prostate carcinoma cells with two different HDACis (trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA)) induced EMT phenotype mediated through up-regulation of transcription factors ZEB1, ZEB2 and Slug, increased expression of mesenchymal markers vimentin, N-cadherin and fibronectin by promoting histone 3 acetylation on gene promoters.  In addition TSA increased the stem cell markers Sox2 and Nanog with concomitant EMT morphology and increased cell motility.

Below is the abstract of this paper(1):


Clinical experience of histone deacetylase inhibitors (HDACIs) in patients with solid tumors has been disappointing; however, the molecular mechanism of treatment failure is not known. Therefore, we sought to investigate the molecular mechanism of treatment failure of HDACIs in the present study. We found that HDACIs Trichostatin A (TSA) and Suberoylanilide hydroxamic acid (SAHA) could induce epithelial-to-mesenchymal transition (EMT) phenotype in prostate cancer (PCa) cells, which was associated with changes in cellular morphology consistent with increased expression of transcription factors ZEB1, ZEB2 and Slug, and mesenchymal markers such as vimentin, N-cadherin and Fibronectin. CHIP assay showed acetylation of histone 3 on proximal promoters of selected genes, which was in part responsible for increased expression of EMT markers. Moreover, TSA treatment led to further increase in the expression of Sox2 and Nanog in PCa cells with EMT phenotype, which was associated with cancer stem-like cell (CSLC) characteristics consistent with increased cell motility. Our results suggest that HDACIs alone would lead to tumor aggressiveness, and thus strategies for reverting EMT-phenotype to mesenchymal-to-epithelial transition (MET) phenotype or the reversal of CSLC characteristics prior to the use of HDACIs would be beneficial to realize the value of HDACIs for the treatment of solid tumors especially PCa.

Highlights of the research include:

  • TSA and SAHA induce morphologic changes  in prostate carcinoma LNCaP and PC3 cells related to EMT by microscopy as well as accumulation of mesenchymal markers ZEB1, vimentin, and F-actin reorganization shown by immunofluorescence microscopy and increased expression of these markers shown by real-time PCR
  • Western blotting showed TSA treatment resulted in hyperacetyulation of histone 3 whi8le CHIP analysis revealed increased histone 3 acetylation on the promoters of vimentin, ZEB2, Slug, and MMP2
  • Western analysis revealed that HDACi not only induced EMT but increased the expression of cancer stem cell markers associated with increased motility such as Sox2 and Nanog.  Increased cell migration was measured by Transwell migration assays and increased cell motility was measured via cell detachment assays

1.            Kong, D., Ahmad, A., Bao, B., Li, Y., Banerjee, S., and Sarkar, F. H. (2012) PloS one 7, e45045

2.            Bertino, E. M., and Otterson, G. A. (2011) Expert opinion on investigational drugs 20, 1151-1158

3.            Robey, R. W., Chakraborty, A. R., Basseville, A., Luchenko, V., Bahr, J., Zhan, Z., and Bates, S. E. (2011) Molecular pharmaceutics 8, 2021-2031

4.            Wang, Z., Li, Y., Kong, D., Banerjee, S., Ahmad, A., Azmi, A. S., Ali, S., Abbruzzese, J. L., Gallick, G. E., and Sarkar, F. H. (2009) Cancer research 69, 2400-2407

5.            Wang, Z., Li, Y., Ahmad, A., Azmi, A. S., Kong, D., Banerjee, S., and Sarkar, F. H. (2010) Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 13, 109-118

6.            Hugo, H., Ackland, M. L., Blick, T., Lawrence, M. G., Clements, J. A., Williams, E. D., and Thompson, E. W. (2007) Journal of cellular physiology 213, 374-383

7.            Thiery, J. P. (2002) Nature reviews. Cancer 2, 442-454

8.            Kong, D., Banerjee, S., Ahmad, A., Li, Y., Wang, Z., Sethi, S., and Sarkar, F. H. (2010) PloS one 5, e12445

9.            Kong, D., Li, Y., Wang, Z., and Sarkar, F. H. (2011) Cancers 3, 716-729

10.          Bao, B., Wang, Z., Ali, S., Kong, D., Li, Y., Ahmad, A., Banerjee, S., Azmi, A. S., Miele, L., and Sarkar, F. H. (2011) Cancer letters 307, 26-36

Other research papers on Cancer and Cancer Therapeutics were published on this Scientific Web site as follows:

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

Nanotechnology Tackles Brain Cancer

Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling: a MED12 Control

Personalized medicine-based cure for cancer might not be far away

GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

Lung Cancer (NSCLC), drug administration and nanotechnology

Non-small Cell Lung Cancer drugs – where does the Future lie?

Cancer Innovations from across the Web

arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data

How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

mRNA interference with cancer expression

Search Results for ‘cancer’ on this web site

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Lipid Profile, Saturated Fats, Raman Spectrosopy, Cancer Cytology

mRNA interference with cancer expression

Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed

Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Crucial role of Nitric Oxide in Cancer

Targeting Glucose Deprived Network Along with Targeted Cancer Therapy Can be a Possible Method of Treatment

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