DepMap

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

adicorat — Wed, 05 Feb 2025 16:00:00 +0000

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

By Allessandra DiCorato February 5, 2025

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Targeting the PELO gene could be a way to kill tumor cells in cancers with one of two common genetic mutations.

By Allessandra DiCorato

February 5, 2025

Credit: Natalie Velez, ӳ��ý Communications

Scientists from the Cancer Dependency Map (DepMap) at the ӳ��ý of MIT and Harvard and Columbia University have discovered that about 5 percent of adult cancers rely heavily on a gene called PELO to survive and that disabling the gene kills those cancer cells. These cancers have mutations in one of two genes, FOCAD or TTC37.

The finding, described today in Nature, is a new synthetic lethality — a pair of genetic changes that together kill cancer cells. The researchers say that PELO is a promising target, and that genetic testing could identify cancer patients with FOCAD or TTC37 mutations who would benefit from new PELO-targeting drugs.

“These cancers are a huge unmet medical need, because we don’t have effective drugs for them,” said Francisca Vazquez, co-senior author on the study along with postdoctoral researcher Edmond Chan, now an assistant professor at Columbia University. Vazquez is also director of DepMap, which systematically probes cancer cell lines for genetic vulnerabilities.

“Targeting synthetic lethalities is a good way to expand the repertoire of tumors we’re able to treat,” Vazquez said. “This new synthetic lethality we found shows how powerful the DepMap datasets can be.”

Patricia Borck, a DepMap research scientist in ӳ��ý’s Cancer Program, is first author on the study.

Lethal pairings

The team began by looking for ways to target a common set of cancers in which both copies of chromosome 9 have a deletion in a region called 9p21.3. These mutations occur in a range of deadly cancers including those of the brain, bladder, pancreas, esophagus, and lungs.

The scientists analyzed datasets from DepMap’s genome-wide CRISPR knockout screens in more than 1,200 cell lines. They noticed that cell lines with very few copies of the 9p21.3 sequence died when PELO was disabled. They then found that deletions within the FOCAD gene specifically caused the cells’ dependency on PELO.

But the cells with 9p21.3 deletions were not the only ones with a PELO dependency. Another group of cells with high microsatellite instability — mutations in short repeated DNA sequences, specifically in the TTC37 gene — had the same sensitivity. That meant there are potentially two groups of patients who might benefit from drugs targeting PELO: those with deletions in FOCAD and others with deletions in TTC37, which are found in colorectal and endometrial tumors.

Superkiller complexes

Next, Vazquez, Chan, and their team wanted to understand why mutations in FOCAD and TTC37 left cells vulnerable to PELO loss. PELO encodes a protein responsible for restarting ribosomes when they stall on defective mRNA sequences during protein production. The FOCAD and TTC37 proteins are part of — and help stabilize — an assembly called the “superkiller complex,” which extracts RNA from stalled ribosomes.

In the lab, the researchers found that cells with lower levels of the FOCAD and TTC37 proteins were more dependent on PELO. This suggests that cells compensate for mutations in the FOCAD and TTC37 proteins by using PELO to restart stalled ribosomes. But without PELO, cells aren’t able to restart protein production and eventually die.

Next, the team wants to better understand the role both PELO and the superkiller complex play in human cells. They also aim to pinpoint the degree to which a new drug would need to inhibit PELO to be therapeutically effective.

Vazquez thinks it’s possible that there are other genes that may have synthetic lethality relationships with PELO, which could further expand the range of patients who might benefit from a potential drug.

Funding

This work was supported in part by the National Institutes of Health, the Robertson Foundation, and the Dependency Map Consortium.

Paper cited

Borck, PC et al. Impaired SKI complex in 9p21.3-deleted or MSI-H cancers confers synthetic lethality with PELO loss. Nature. Online February 5, 2025. DOI: 10.1038/s41586-024-08509-3.

Tags:

Cancer

DepMap

Some CRISPR screens may be missing cancer drug targets

adicorat — Fri, 14 Jun 2024 13:00:00 +0000

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

By Allessandra DiCorato February 5, 2025

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Targeting the PELO gene could be a way to kill tumor cells in cancers with one of two common genetic mutations.

By Allessandra DiCorato

February 5, 2025

Credit: Natalie Velez, ӳ��ý Communications

Patricia Borck, a DepMap research scientist in ӳ��ý’s Cancer Program, is first author on the study.

Lethal pairings

Superkiller complexes

Funding

This work was supported in part by the National Institutes of Health, the Robertson Foundation, and the Dependency Map Consortium.

Paper cited

Borck, PC et al. Impaired SKI complex in 9p21.3-deleted or MSI-H cancers confers synthetic lethality with PELO loss. Nature. Online February 5, 2025. DOI: 10.1038/s41586-024-08509-3.

Tags:

Cancer

DepMap

ӳ��ý, Dana-Farber, St. Jude join together to drive progress against pediatric cancer

tulrich@broadinstitute.org — Thu, 13 Oct 2022 10:00:52 +0000

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

By Allessandra DiCorato February 5, 2025

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Targeting the PELO gene could be a way to kill tumor cells in cancers with one of two common genetic mutations.

By Allessandra DiCorato

February 5, 2025

Credit: Natalie Velez, ӳ��ý Communications

Patricia Borck, a DepMap research scientist in ӳ��ý’s Cancer Program, is first author on the study.

Lethal pairings

Superkiller complexes

Funding

This work was supported in part by the National Institutes of Health, the Robertson Foundation, and the Dependency Map Consortium.

Paper cited

Borck, PC et al. Impaired SKI complex in 9p21.3-deleted or MSI-H cancers confers synthetic lethality with PELO loss. Nature. Online February 5, 2025. DOI: 10.1038/s41586-024-08509-3.

Tags:

Cancer

DepMap

ӳ��ý Discovery Center in Cambridge opens to the public this October

kzusi@broadinstitute.org — Mon, 19 Sep 2022 14:53:09 +0000

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

By Allessandra DiCorato February 5, 2025

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Targeting the PELO gene could be a way to kill tumor cells in cancers with one of two common genetic mutations.

By Allessandra DiCorato

February 5, 2025

Credit: Natalie Velez, ӳ��ý Communications

Patricia Borck, a DepMap research scientist in ӳ��ý’s Cancer Program, is first author on the study.

Lethal pairings

Superkiller complexes

Funding

This work was supported in part by the National Institutes of Health, the Robertson Foundation, and the Dependency Map Consortium.

Paper cited

Borck, PC et al. Impaired SKI complex in 9p21.3-deleted or MSI-H cancers confers synthetic lethality with PELO loss. Nature. Online February 5, 2025. DOI: 10.1038/s41586-024-08509-3.

Tags:

Cancer

DepMap

New protein complex structure reveals possible ways to target key cancer pathway

aviveros@broadinstitute.org — Wed, 13 Jul 2022 05:04:00 +0000

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

By Allessandra DiCorato February 5, 2025

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Targeting the PELO gene could be a way to kill tumor cells in cancers with one of two common genetic mutations.

By Allessandra DiCorato

February 5, 2025

Credit: Natalie Velez, ӳ��ý Communications

Patricia Borck, a DepMap research scientist in ӳ��ý’s Cancer Program, is first author on the study.

Lethal pairings

Superkiller complexes

Funding

This work was supported in part by the National Institutes of Health, the Robertson Foundation, and the Dependency Map Consortium.

Paper cited

Borck, PC et al. Impaired SKI complex in 9p21.3-deleted or MSI-H cancers confers synthetic lethality with PELO loss. Nature. Online February 5, 2025. DOI: 10.1038/s41586-024-08509-3.

Tags:

Cancer

DepMap

Researchers find genetic “Achilles heel” in ovarian and uterine cancers

adicorat — Tue, 19 Apr 2022 13:40:12 +0000

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

By Allessandra DiCorato February 5, 2025

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Targeting the PELO gene could be a way to kill tumor cells in cancers with one of two common genetic mutations.

By Allessandra DiCorato

February 5, 2025

Credit: Natalie Velez, ӳ��ý Communications

Patricia Borck, a DepMap research scientist in ӳ��ý’s Cancer Program, is first author on the study.

Lethal pairings

Superkiller complexes

Funding

This work was supported in part by the National Institutes of Health, the Robertson Foundation, and the Dependency Map Consortium.

Paper cited

Borck, PC et al. Impaired SKI complex in 9p21.3-deleted or MSI-H cancers confers synthetic lethality with PELO loss. Nature. Online February 5, 2025. DOI: 10.1038/s41586-024-08509-3.

Tags:

Cancer

DepMap

Dependency Map team releases Celligner to help match tumors and cell lines for research

tulrich@broadinstitute.org — Mon, 04 Jan 2021 19:33:53 +0000

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

By Allessandra DiCorato February 5, 2025

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Targeting the PELO gene could be a way to kill tumor cells in cancers with one of two common genetic mutations.

By Allessandra DiCorato

February 5, 2025

Credit: Natalie Velez, ӳ��ý Communications

Patricia Borck, a DepMap research scientist in ӳ��ý’s Cancer Program, is first author on the study.

Lethal pairings

Superkiller complexes

Funding

This work was supported in part by the National Institutes of Health, the Robertson Foundation, and the Dependency Map Consortium.

Paper cited

Borck, PC et al. Impaired SKI complex in 9p21.3-deleted or MSI-H cancers confers synthetic lethality with PELO loss. Nature. Online February 5, 2025. DOI: 10.1038/s41586-024-08509-3.

Tags:

Cancer

DepMap

New genetic vulnerability found in upwards of a third of all cancers

tulrich@broadinstitute.org — Tue, 15 Dec 2020 16:00:00 +0000

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

By Allessandra DiCorato February 5, 2025

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Targeting the PELO gene could be a way to kill tumor cells in cancers with one of two common genetic mutations.

By Allessandra DiCorato

February 5, 2025

Credit: Natalie Velez, ӳ��ý Communications

Patricia Borck, a DepMap research scientist in ӳ��ý’s Cancer Program, is first author on the study.

Lethal pairings

Superkiller complexes

Funding

This work was supported in part by the National Institutes of Health, the Robertson Foundation, and the Dependency Map Consortium.

Paper cited

Borck, PC et al. Impaired SKI complex in 9p21.3-deleted or MSI-H cancers confers synthetic lethality with PELO loss. Nature. Online February 5, 2025. DOI: 10.1038/s41586-024-08509-3.

Tags:

Cancer

DepMap

Study eyes partially-lost essential genes as possible targets in cancer

tulrich@broadinstitute.org — Fri, 22 May 2020 11:59:00 +0000

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

By Allessandra DiCorato February 5, 2025

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Targeting the PELO gene could be a way to kill tumor cells in cancers with one of two common genetic mutations.

By Allessandra DiCorato

February 5, 2025

Credit: Natalie Velez, ӳ��ý Communications

Patricia Borck, a DepMap research scientist in ӳ��ý’s Cancer Program, is first author on the study.

Lethal pairings

Superkiller complexes

Funding

This work was supported in part by the National Institutes of Health, the Robertson Foundation, and the Dependency Map Consortium.

Paper cited

Borck, PC et al. Impaired SKI complex in 9p21.3-deleted or MSI-H cancers confers synthetic lethality with PELO loss. Nature. Online February 5, 2025. DOI: 10.1038/s41586-024-08509-3.

Tags:

Cancer

DepMap

Analysis of CRISPR-cas9 datasets leads to largest genetic screen resource for cancer research

David Cameron — Fri, 20 Dec 2019 16:21:03 +0000

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

By Allessandra DiCorato February 5, 2025

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Targeting the PELO gene could be a way to kill tumor cells in cancers with one of two common genetic mutations.

By Allessandra DiCorato

February 5, 2025

Credit: Natalie Velez, ӳ��ý Communications

Patricia Borck, a DepMap research scientist in ӳ��ý’s Cancer Program, is first author on the study.

Lethal pairings

Superkiller complexes

Funding

This work was supported in part by the National Institutes of Health, the Robertson Foundation, and the Dependency Map Consortium.

Paper cited

Borck, PC et al. Impaired SKI complex in 9p21.3-deleted or MSI-H cancers confers synthetic lethality with PELO loss. Nature. Online February 5, 2025. DOI: 10.1038/s41586-024-08509-3.

Tags:

Cancer

DepMap

DepMap

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Lethal pairings

Superkiller complexes

Some CRISPR screens may be missing cancer drug targets

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Lethal pairings

Superkiller complexes

ӳ����ý, Dana-Farber, St. Jude join together to drive progress against pediatric cancer

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Lethal pairings

Superkiller complexes

ӳ����ý Discovery Center in Cambridge opens to the public this October

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Lethal pairings

Superkiller complexes

New protein complex structure reveals possible ways to target key cancer pathway

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Lethal pairings

Superkiller complexes

Researchers find genetic “Achilles heel” in ovarian and uterine cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Lethal pairings

Superkiller complexes

Dependency Map team releases Celligner to help match tumors and cell lines for research

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Lethal pairings

Superkiller complexes

New genetic vulnerability found in upwards of a third of all cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Lethal pairings

Superkiller complexes

Study eyes partially-lost essential genes as possible targets in cancer

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Lethal pairings

Superkiller complexes

Analysis of CRISPR-cas9 datasets leads to largest genetic screen resource for cancer research

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Mutations in two gene pairs point to a promising drug target in 5 percent of adult cancers

Lethal pairings

Superkiller complexes

ӳ��ý, Dana-Farber, St. Jude join together to drive progress against pediatric cancer

ӳ��ý Discovery Center in Cambridge opens to the public this October