Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please can you give an introduction to the epidermal growth factor receptor (EGFR) and outline what was previously known about drug resistant brain tumors?
In cancer, mutations in proteins that control cell growth are common, leading to unrestrained cellular proliferation and tumor formation.
The epidermal growth factor receptor (EGFR) is one such protein that is commonly mutated in cancer, including with a high frequency in the highly malignant brain cancer known as glioblastoma.
Despite the dependence of glioblastomas on this mutation, drugs devised to block EGFR’s signaling work in only a small subset of patients, and in those patients who do respond, the drugs tend to work for only for a short while, until the cancer cells adapt to evade the therapy.
So far, much of the research examining such drug resistance has focused on how mutations of other proteins in cancer cells allow them to resist drugs, but we know that not all drug-resistant tumors harbor those additional mutations, suggesting that they have evolved alternative resistance mechanisms.
What did your study find? Could you please outline how some glioblastoma cells have developed resistance to drugs that target EGFR signaling by hijacking the signaling of platelet-derived growth factor receptor-β (PDGFRβ), a cell surface receptor?
Our study identifies a unique mechanism by which glioblastoma cells develop resistance to drugs that target EGFR signaling.
What was most surprising for us was to find that the cells accomplish this feat not through mutation, but by hijacking the signaling of a perfectly normal cell surface receptor named platelet-derived growth factor receptor-β (PDGFRβ).
Targeting both receptors at once is what prevents resistance and suppresses glioblastoma tumors in laboratory models.
How did your research discover this?
We began our study by exploring how blocking EGFR alters signaling in glioblastoma cells. To do so, we transplanted glioblastoma tumors that are naturally fueled by a permanently activated mutant of EGFR into mice. We then treated the mice with a drug named erlotinib, which inhibits EGFR.
Much to our surprise, one receptor in particular—PDGFRβ—was highly expressed and active in all treated tumor cells, but absent in tumors that were not treated. We detected the same pattern in cultures of cells derived from a variety of glioblastoma tumors.
This suggested that cancer cells in which EGFR signaling is blocked respond by expressing PDGFRβ to compensate for the loss of that critical signal. And we confirmed this by examining tumor samples in people undergoing treatment with EGFR-targeting drugs.
Importantly, PDGFRβ is not frequently amplified or mutated in glioblastoma, therefore we searched for alternative mechanisms by which the tumor cells could hijack PDGFRβ.
Using various techniques to tease apart the signaling pathways responsible for this effect, we found that two distinct biochemical circuits switched on by EGFR, suppressed the expression of the PDGFRβ gene.
One is mediated by a protein named mTORC1, and another by a protein named MEK. When one blocks EGFR signaling with a drug, that repression is lifted. But, more importantly, these tumors do not need PDGFRβ signaling to survive until you block EGFR. At that point, the tumors become highly dependent on PDGFRβ.
Why are drug resistance mechanisms very difficult to anticipate?
Acquired resistance to tyrosine kinase inhibitors (TKI) represents a major challenge for personalized cancer therapy. If the seeds of resistance, such as other mutated growth factor receptors exist in even a small fraction of the tumor before treatment, then applying advanced molecular techniques to detect it could enable us to anticipate the mechanisms of resistance.
However, if cancer cells rewire their circuitry to hijack normal, physiologically regulated growth factor receptors and their downstream effectors, then anticipating drug resistance becomes a greater challenge.
It’s almost like a game of whack-a-mole. You use a drug to suppress a choice target, and something else pops up to take its place and keep the cells alive—in this case a growth factor receptor that is perfectly normal in physiological terms. Notably, such resistance mechanisms, unlike genetic mutation, are very difficult to anticipate.
This is why research is under way to better understand multidrug resistance in cancer and to find drugs that may block or reverse the development of drug resistance in cancer cells.
Why are growth signals so critical to the survival of cancer cells?
Growth signals, which are typically transduced through growth factor receptors, are tightly regulated in normal healthy cells. This tight regulation enables sufficient cell growth to maintain function and cellular turnover; however if it becomes unrestrained, cancer will arise.
Thus, mutations in growth factor receptors and their downstream effectors are instrumental in causing human cancer.
What implications do the results of your research have for brain cancers and other cancers?
Our findings highlight the remarkable adaptability of cancer cells and how they harness multiple mechanisms to maintain the growth signals critical to their survival. These results also point to a specific mechanism of resistance that can be anticipated and potentially targeted.
Further, aberrant EGFR signaling drives many types of tumors in addition to glioblastoma, therefore, other types of cancer could potentially develop this type of resistance mechanisms.
We hope to work collaboratively across the Ludwig community to explore small molecule inhibitors of PDGFRβ and to examine whether similar drug resistance mechanisms are found in other cancers as well.
How far do you think we are from being able to prevent drug resistance in brain tumors and other cancers? What further research needs to be carried out on drug resistant brain tumors?
The cancer genome atlas and other efforts to provide a map of the mutational landscape of brain tumors, coupled with a substantial body of research focusing on frequent mutational targets like EGFR, has led to a much deeper understanding of what some of the key drug targets are.
The type of work done in this study, sheds light on how tumors function to evade therapy by using alternative routes to maintain flux to key downstream growth signals.
This type of functional understanding may lead towards more effective combination approaches to suppress the tumor, potentially leading to far better outcomes for patients.
The next step is to test in clinical trials how targeting both receptors affects the treatment of glioblastoma.
Where can readers find more information?
The paper has been published ahead of print in Cancer Discovery.
De-repression of PDGFRβ transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients
David Akhavan, Alexandra L. Pourzia, Alex A. Nourian, Kevin J. Williams, David Nathanson, Ivan Babic, Genaro R. Villa, Kazuhiro Tanaka, Ali Nael, Huijun Yang, Julie Dang, Harry V. Vinters, William H. Yong, Mitchell Flagg, Fuyuhiko Tamanoi, Takashi Sasayama, C. David James, Harley I. Kornblum, Tim F. Cloughesy, Webster K. Cavenee, Steven J. Bensinger and Paul S. Mischel. Cancer Discovery. 2013 March 26.
About Prof. Mischel and Prof. Bensinger
Dr. Paul Mischel heads Ludwig San Diego’s Laboratory of Molecular Pathology and also holds a professorship in the UCSD Department of Pathology.
Dr. Mischel is a board certified neuropathologist with expertise in signal transduction biology. His laboratory has expertise in quantitative analysis of signal transduction pathways, stem-cell related pathways, and gene expression networks in clinical samples.
He is a member of the American Society for Clinical Investigation (ASCI), past President (2010-2011) of the ASCI and Ludwig Institute for Cancer Research Member based at UCSD.
Dr. Mischel graduated Alpha Omega Alpha with an M.D. from Cornell University Medical College and trained in Anatomic Pathology and Neuropathology at UCLA.
He obtained his post-doctoral research training in the laboratory of Dr. Louis F. Reichardt at the Howard Hughes Medical Institute at UCSF and joined the UCLA faculty in 1998.
Dr. Mischel has received a number of awards, including the Farber Award in 2007, the top brain tumor research award given jointly by the Society for Neuro-oncology and the American Association of Neurosurgery. Dr. Mischel's work was profiled by the Journal of Cell Biology in June 2008.
Dr. Steven Bensinger is an Assistant Professor at the Institute for Molecular Medicine and the Department of Pathology and Laboratory Medicine at the University of California, Los Angeles and a member of Jonsson Comprehensive Cancer Center’s (JCCC) Signal Transduction and Therapeutics Program Area at UCLA.
His laboratory is focused on understanding how metabolism controls the growth and survival of normal and cancer cells.
He holds professional membership in the following: American Association of Immunologists, American Association of Veterinary Immunologists and American Heart Association.
Dr. Bensinger graduated (Summa Cum Laude) from University of Pennsylvania School of Veterinary Medicine and holds a doctoral degree from the University of Pennsylvania School of Biomedical Graduate Studies.
He obtained his post-doctoral research training in the laboratory of Dr. Peter Tontonoz at the Howard Hughes Medical Institute at UCLA and joined the UCLA faculty in 2008.
Dr. Bensinger has received several awards including the Dean’s Scholarship for his academic achievement, the Leonard Pearson Award from the University of Pennsylvania for his outstanding research potential and the 2012 Sontag Foundation Distinguished Scientific Award, given to early career scientists in the field of brain cancer.