From Broad Institute: “Cancer drug resistance-from laundry list to paradigms”

Broad Institute

Broad Institute

March 20th, 2015
Lisa Girard

Image by Broad Communications

Drug resistance is one of the greatest obstacles to effective cancer therapy. Research has shown that cancer cells can use any number of genes and strategies to achieve or acquire resistance to particular therapies. Until recently, scientists have taken a piecemeal approach to understanding the problem of resistance—unraveling individual mechanisms without reaching any kind of overarching theme.

“In terms of resistance to targeted therapy there are a lot of publications—a laundry list of mechanisms. It can make you bleary-eyed,” says Broad Institute member Levi Garraway. “We know a gazillion ways to develop resistance, but how does that knowledge help us develop better therapeutic regimens?”

Garraway and his colleagues suspect that individual resistance mechanisms often coalesce into common cellular downstream effects. For example, half of all melanoma cancers have a mutation in a signaling factor called BRAF. BRAF then signals to another factor, MEK, which signals to another factor called ERK, which then triggers cell growth. The current treatment for this type of cancer uses a combination of BRAF and MEK inhibitors to shut the pathway down. There are several different resistance mechanisms, but many have the same effect: they are able to switch on ERK.

In the broadest sense, resistance mechanisms could be put into three main categories 1) a pathway gets turned back on; 2) a pathway is bypassed; or 3) a cell enters an alternative cell state in which the pathway is no longer relevant.

“We actually don’t think it’s a laundry list of mechanisms,” says Garraway. “We think that by mapping out the landscape of resistance we will be able to learn that while there might be 50, 60, 70, or more individual genes that can cause resistance, they actually converge onto a smaller number of common cellular effects.” The aim is to understand the networks in a cell that are critical for the drug resistant state, and identify targets where many signals converge.

In the hope of understanding the functional landscape of resistance, Broad researcher and first author Rick Wilson, Garraway, and colleagues looked at the ability of over 12,000 genes to confer resistance to inhibitors of oncogenic ALK in ALK-dependent lung cancer. Their goal was to identify functional categories of resistance genes, as well as identify new genes.

Results of the study, recently published in Cancer Cell, identify a number of genes known to play a role in other types of drug-resistant cancer, including kinases, adaptor molecules, and transcription factors, but as the researchers suspected, they also point to a previously undetected pathway parallel to the MAPK pathway that starts with a family of G protein coupled receptors called purinergic receptors. The resistance mechanism linked to those receptors appeared, at least in part, to go through a signaling molecule called Protein Kinase C (PKC). Similar to the effect of ERK in melanoma, switching on PKC alone triggered significant resistance in cellular models.

While many current therapies target upstream pathway components, this study demonstrates the potential usefulness of therapeutically targeting factors closer to the transcriptional output.

“By targeting critical downstream components, potential upstream resistance mechanisms may no longer be sufficient to drive resistance,” says Wilson. Wilson believes that detailed characterization of patient tumors may provide insight in terms of prioritizing some pathways over others.

How can these findings ultimately translate into better cancer therapy regimens? In the past, scientists sought to understand resistance mechanisms so that if a tumor did become resistant, it would be possible to make it sensitive again. Now the goals have shifted to account for the heterogeneous and multifactorial nature of tumors, and understanding resistance is critical so that patients can receive combination therapies up front to avoid or delay resistance in the first place.

“With a global understanding we can start to piece together the networks that matter for achieving resistance to oncogene-directed therapy,” says Garraway. “Eventually, this understanding will help us develop new therapeutic combinations to overcome these mechanisms.”

Other scientists contributing to this work include Cory M. Johannessen, Federica Piccioni, Pablo Tamayo, Jong Wook Kim, Eliezer M. Van Allen, Steven M. Corsello, Marzia Capelletti, Antonio Calles, Mohit Butaney, Tanaz Sharifnia, Stacey B. Gabriel, Jill P. Mesirov, William C. Hahn, Jeffrey A. Engelman, Matthew Meyerson, David E. Root, and Pasi A. Jänne.

Wilson F, et al. A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer. Cancer Cell. 27, 397-408 (9 March 2015). DOI:

See the full article here.

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