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Researchers Develop Resource Tying Cancer Gene Characteristics to Small Molecule Sensitivities

NEW YORK (GenomeWeb News) – In Cell this week, researchers led by the Broad Institute's Stuart Schreiber presented a resource that correlates the genetic characteristics of a few hundred cancer cell lines to their sensitivity to a number of small molecules.

To develop the Cancer Therapeutics Response Portal, Schreiber and his colleagues profiled the sensitivity of 242 genetically characterized cancer cell lines to more than 350 small molecules with well-described targets and activities.

"Genomic and lineage [cancer cell line] profiling offers an approach to identify cancer dependencies that are targetable with small molecules and suggest combinations of compounds that mitigate drug resistance," the researchers wrote. "The Cancer Therapeutic Response Portal suggests candidate dependencies associated with common and medically significant oncogenes."

For example, they focused in on mutations linked to sensitivity to navitoclax, a Bcl-2 family antagonist, finding a potential association between activating mutations in beta-catenin and sensitivity to that drug.

The cell lines in the CTRP included ones studied by The Cancer Genome Atlas and by genome-wide RNAi screens, and are a subset of the thousand or so that are part of the Cancer Cell Line Encyclopedia. In addition, the compounds comprising the Informer Set included 35 drugs approved by the US Food and Drug Administration, 54 clinical candidates, and 265 probes.

The cells were grown on media and treated with the compounds at a variety of concentrations for 72 hours before their sensitivity to those treatments were determined.

"Whereas most CCLs respond differentially across our Informer Set, we observed that CCLs within specific tissue lineages and suspension CCLs were often more sensitive to many compounds tested," the investigators noted.

Further, they were able to identify a number of known mutation-based sensitivities. For example, they found that BRAF mutant lines had increased sensitivity to vemurafenib, the BRAF-V600E inhibitor approved by FDA. In addition, NRAS mutant and KRAS mutant lines have increased sensitivity to the MEK1/2 inhibitor selumetinib, which has shown some activity in clinical trials, the researchers noted.

Schreiber and his colleagues were also able to home in on novel genetic-based sensitivities. For instance, they saw that lines harboring MYC mutations had an increased sensitivity to the green tea-derived (–)-gallocatechin-3-monogallate as well as to a chemokine receptor inhibitor called SB-225002.

Overall, certain mutations indicated that a line is resistant to many compounds. For instance, mutations in STK11, EGFR, and BRAF all correlated with non-responsiveness to a number of compounds.

Meanwhile, Schreiber and his colleagues particularly examined which molecules CTNNB1 mutant lines were sensitive to, as mutations in CTNNB1, the transcription factor b-catenin gene, are found in a number of cancers, though a targeted treatment aimed at them has yet to be found.

Those mutant lines, the researchers found, are among the most sensitive to navitoclax, which inhibits anti-apoptotic Bcl-2 family members. Additionally, they found other mutations — in AXIN1 and CSNK1A1 — were also correlated with sensitivity to the drug.

To confirm this finding, Schreiber and his colleagues developed a parsimonious model to predict navitoclax sensitivity, and CTNNB1 was at the top of the list of features that rank such sensitivity.

Additionally, they re-tested a number of lines for navitoclax sensitivity, finding similar results to their original assay. The most sensitive lines, they pointed out, showed a large increase in caspase 3/7 activation, which indicated that apoptosis was the source of their decline in viability. They also tested the sensitivity of CTNNB1 mutant lines harboring mutations in their degradation boxes and saw that they had sensitivity levels similar to the other mutant lines.

"These data support our hypothesis that mutations in CTNNB1 and alterations in its destruction complex are biomarkers for sensitivity to navitoclax," the researchers said.

They added that as CTNNB1 mutations appear to increase b-catenin protein levels, any small molecule that increases b-catenin protein levels could sensitize cells without the navitoclax mutation to the drug. Indeed, they found that they could induce navitoclax sensitivity in eight of the 41 lines they tried.

Schreiber and his colleagues pointed out that navitoclax has been tested in phase I/II clinical trials for small-cell lung cancer, but they argued that it might be better suited against other tumor types. "[O]ur data suggest that navitoclax might best be targeted to patients harboring CTNNB1 mutations, which are present in colorectal, hepatocellular, gastric, and endometrial cancers," they said. "We observe that CTNNB1 mutant CCLs are sensitive to navitoclax in several lineages though more strongly in some (e.g., gastric) than others."

The Cancer Therapeutics Response Portal is available at the Broad's website, and the researchers said that they plan to include additional data — they are testing more drugs and probes — in it when such data become available.

"Our hope is that the cancer biology community will use the CTRP to identify hypotheses for deeper investigation and to accelerate discovery of patient-targeted therapies with better treatment outcomes," Schreiber and his colleagues added.