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Researchers say they’ve discovered key events that prompt drug resistance in myeloproliferative neoplasms (MPNs) and certain solid tumor malignancies.
By mapping the steps that myelofibrosis, melanoma, and breast cancer cells use to become resistant to drugs, the investigators believe they have identified better targets for blocking those pathways to ensure current therapies are effective.
The groups reported these findings in two papers published in Science Signaling.
“In our studies, we developed a screening technology that allows us to quickly identify the routes cells can use to become resistant, and, using that information, we were able to show that these mechanisms seen in the laboratory are actually also occurring in patients’ tumors,” said Kris Wood, PhD, an assistant professor at Duke University in Durham, North Carolina, and senior author of both studies.
In the first study, Dr Wood and his colleagues conducted a broad survey of the known cell-signaling pathways that, when activated, have the potential to trigger drug resistance.
Using this screening technology, the researchers were able to corroborate the results of earlier drug-resistance studies, while also finding pathways that had not previously been described.
The team identified the MAPK and PI3K pathways, which are known to mediate drug resistance. But they also found that activation of the Notch1 pathway caused drug resistance, and inhibiting Notch1 signaling restored drug efficacy.
“Interestingly, the mechanisms are quite similar among all 3 of the cancer types,” Dr Wood noted. “In breast cancer and melanoma, our findings suggest the same Notch1 pathway as a potential driver of resistance to a wide array of targeted therapies—a role that has not been widely acknowledged previously.”
The investigators found that Notch signaling mediated drug resistance to an estrogen receptor-targeted therapy used in breast cancer and to a kinase-targeted therapy used in melanoma. And tumors from some patients with relapsed breast cancer or melanoma had increased markers of Notch1 signaling.
In the second study, the researchers used the aforementioned pathway-centric screen to track a pair of separate signaling pathways downstream of RAS, a protein frequently activated in MPNs.
The team found the pathway mediated by RAS promoted drug resistance in hematopoietic cell lines containing an activating mutation in JAK2. And RAS signaling led to the phosphorylation-mediated inactivation of the pro-apoptotic protein BAD, which enabled cell survival.
Combining JAK inhibitors with inhibitors of kinases downstream of RAS signaling prompted apoptosis in cell lines that were resistant to JAK inhibitors. This suggests such combinations may be effective for treating drug-resistant MPNs.
“Together, these findings improve our ability to stratify patients into groups more and less likely to respond to therapy and design drug combinations that work together to block or delay resistance,” Dr Wood concluded. 
Researchers say they’ve discovered key events that prompt drug resistance in myeloproliferative neoplasms (MPNs) and certain solid tumor malignancies.
By mapping the steps that myelofibrosis, melanoma, and breast cancer cells use to become resistant to drugs, the investigators believe they have identified better targets for blocking those pathways to ensure current therapies are effective.
The groups reported these findings in two papers published in Science Signaling.
“In our studies, we developed a screening technology that allows us to quickly identify the routes cells can use to become resistant, and, using that information, we were able to show that these mechanisms seen in the laboratory are actually also occurring in patients’ tumors,” said Kris Wood, PhD, an assistant professor at Duke University in Durham, North Carolina, and senior author of both studies.
In the first study, Dr Wood and his colleagues conducted a broad survey of the known cell-signaling pathways that, when activated, have the potential to trigger drug resistance.
Using this screening technology, the researchers were able to corroborate the results of earlier drug-resistance studies, while also finding pathways that had not previously been described.
The team identified the MAPK and PI3K pathways, which are known to mediate drug resistance. But they also found that activation of the Notch1 pathway caused drug resistance, and inhibiting Notch1 signaling restored drug efficacy.
“Interestingly, the mechanisms are quite similar among all 3 of the cancer types,” Dr Wood noted. “In breast cancer and melanoma, our findings suggest the same Notch1 pathway as a potential driver of resistance to a wide array of targeted therapies—a role that has not been widely acknowledged previously.”
The investigators found that Notch signaling mediated drug resistance to an estrogen receptor-targeted therapy used in breast cancer and to a kinase-targeted therapy used in melanoma. And tumors from some patients with relapsed breast cancer or melanoma had increased markers of Notch1 signaling.
In the second study, the researchers used the aforementioned pathway-centric screen to track a pair of separate signaling pathways downstream of RAS, a protein frequently activated in MPNs.
The team found the pathway mediated by RAS promoted drug resistance in hematopoietic cell lines containing an activating mutation in JAK2. And RAS signaling led to the phosphorylation-mediated inactivation of the pro-apoptotic protein BAD, which enabled cell survival.
Combining JAK inhibitors with inhibitors of kinases downstream of RAS signaling prompted apoptosis in cell lines that were resistant to JAK inhibitors. This suggests such combinations may be effective for treating drug-resistant MPNs.
“Together, these findings improve our ability to stratify patients into groups more and less likely to respond to therapy and design drug combinations that work together to block or delay resistance,” Dr Wood concluded.
Researchers say they’ve discovered key events that prompt drug resistance in myeloproliferative neoplasms (MPNs) and certain solid tumor malignancies.
By mapping the steps that myelofibrosis, melanoma, and breast cancer cells use to become resistant to drugs, the investigators believe they have identified better targets for blocking those pathways to ensure current therapies are effective.
The groups reported these findings in two papers published in Science Signaling.
“In our studies, we developed a screening technology that allows us to quickly identify the routes cells can use to become resistant, and, using that information, we were able to show that these mechanisms seen in the laboratory are actually also occurring in patients’ tumors,” said Kris Wood, PhD, an assistant professor at Duke University in Durham, North Carolina, and senior author of both studies.
In the first study, Dr Wood and his colleagues conducted a broad survey of the known cell-signaling pathways that, when activated, have the potential to trigger drug resistance.
Using this screening technology, the researchers were able to corroborate the results of earlier drug-resistance studies, while also finding pathways that had not previously been described.
The team identified the MAPK and PI3K pathways, which are known to mediate drug resistance. But they also found that activation of the Notch1 pathway caused drug resistance, and inhibiting Notch1 signaling restored drug efficacy.
“Interestingly, the mechanisms are quite similar among all 3 of the cancer types,” Dr Wood noted. “In breast cancer and melanoma, our findings suggest the same Notch1 pathway as a potential driver of resistance to a wide array of targeted therapies—a role that has not been widely acknowledged previously.”
The investigators found that Notch signaling mediated drug resistance to an estrogen receptor-targeted therapy used in breast cancer and to a kinase-targeted therapy used in melanoma. And tumors from some patients with relapsed breast cancer or melanoma had increased markers of Notch1 signaling.
In the second study, the researchers used the aforementioned pathway-centric screen to track a pair of separate signaling pathways downstream of RAS, a protein frequently activated in MPNs.
The team found the pathway mediated by RAS promoted drug resistance in hematopoietic cell lines containing an activating mutation in JAK2. And RAS signaling led to the phosphorylation-mediated inactivation of the pro-apoptotic protein BAD, which enabled cell survival.
Combining JAK inhibitors with inhibitors of kinases downstream of RAS signaling prompted apoptosis in cell lines that were resistant to JAK inhibitors. This suggests such combinations may be effective for treating drug-resistant MPNs.
“Together, these findings improve our ability to stratify patients into groups more and less likely to respond to therapy and design drug combinations that work together to block or delay resistance,” Dr Wood concluded.