Journal News

JBC: A promiscuous inhibitor uncovers cancer drug targets

Jonathan Griffin
Aug. 1, 2019

When signaling pathways within cells are triggered, proteins activate like a row of tumbling dominoes until the final protein influences some cellular function. In some tumors, multiple signaling pathways drive cell growth and survival; if one pathway ceases activity, another could continue driving cancerous behavior.

Several clinically approved kinase inhibitors originally were designed to block the function of individual signaling kinase proteins. Scientists now know that some of these inhibitors indiscriminately disrupt numerous proteins, which may allow them to kill certain tumors but also may inhibit some proteins unnecessarily, eliciting adverse effects.

To pinpoint the most therapeutically relevant kinase targets in cancer cells, a group of researchers at Harvard Medical School and the Dana Farber Cancer Institute in Boston, led by Nathanael Gray, has developed a method that exploits the multitargeted nature of a chemical inhibitor.

In a study published in the Journal of Biological Chemistry, Gray and colleagues identified key molecules that support the survival of a specific type of lung cancer. By analyzing how these cells respond to a cancer-killing kinase inhibitor with numerous targets, they showed that the anti-cancer effects likely were elicited by simultaneous inhibition of two signaling pathways. This approach could lead to development of cancer drugs that attack only the right targets.

Nuclei in purple and Cytoplasm in pinkA micrograph of a non–small cell lung carcinoma shows nuclei in purple and cytoplasm in pink.Librepath/Wikimedia CommonsWhile studying various kinase inhibitors, Gray and his lab identified one, known as SM1-71, which binds to dozens of kinases, some of which support cell survival and growth.

“It was sort of like a stick of dynamite and really could hit a lot of different targets,” Gray said.

In the JBC study, the researchers exposed several cancer cell types to SM1-71 and found that the drug was highly toxic to a lung cancer cell line with a mutation that activates many signaling pathways that drive cell growth. The inhibitor’s ability to kill these mutated cells suggested that targets in several pathways were being hit, Gray said.

To discover which of the many buttons pushed by SM1-71 elicited its anti-cancer effects, the researchers used Western blotting to narrow down which signaling proteins related to survival and growth were being blocked in cancer cells, revealing that proteins in two critical pathways were inhibited.

The authors then applied various kinase inhibitors to see if inhibiting any combination of the proteins in these pathways would replicate the cancer-killing effects of SM1-71. In the end, inhibiting MEK1/2 and IGF1R/INSR proteins at the same time demonstrated similar effects, suggesting that these are crucial targets in this lung cancer line, Gray said.

SM1-71 is likely not viable in humans because it binds to too many proteins and could cause collateral damage, Gray said. But uncovering its most important targets within specific pathways is valuable for designing drugs that can shut down multiple signaling pathways, which is necessary in some tumors.

“The next step would be to try to preserve the efficacy-driving targets while getting rid of targets that may be contributing to the toxicology,” Gray said.

Enjoy reading ASBMB Today?

Become a member to receive the print edition monthly and the digital edition weekly.

Learn more
Jonathan Griffin

Jonathan Griffin is a science communicator for all ASBMB journals. Follow him on Twitter.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Predicting PROTAC properties
Feature

Predicting PROTAC properties

Dec. 8, 2022

Best of BMB 2022: Proteolysis-targeting chimeras bring together a drug target protein and a ubiquitin ligase to remove the target from the cell. But sometimes the process stalls out.

Cataloging itty-bitty proteins in large numbers
Feature

Cataloging itty-bitty proteins in large numbers

Dec. 7, 2022

Best of BMB 2022: Ribosome profiling has identified thousands of short protein-coding genes, many in unexpected parts of the genome. Research suggests some play important regulatory roles.

Giant, intricate structures
Feature

Giant, intricate structures

Dec. 6, 2022

Best of BMB 2022: In a “triumph of experimental structural biology,” multiple teams tackle the nuclear pore complex.

Evolutionary constraints on disordered proteins
Feature

Evolutionary constraints on disordered proteins

Dec. 5, 2022

Best of BMB 2022: “There’s evidence that there must be conservation of function — so how does this happen, if the sequence changes so much?”

COVID-19, preprints and journalists
Science Communication

COVID-19, preprints and journalists

Dec. 3, 2022

Researchers find that news stories often fail to mention when studies haven’t been peer reviewed.

From the journals: MCP
Journal News

From the journals: MCP

Dec. 2, 2022

Muscling in on a signaling pathway. Probing weaknesses in the T cell surface. Improving single-cell proteomics two ways. Read about papers on these topics recently published in the journal Molecular & Cellular Proteomics.