Drugging multiple same-allele driver mutations in cancer

Nussinov, Ruth; Zhang, Mingzhen; Maloney, Ryan; Jang, Hyunbum

doi:10.1080/17460441.2021.1905628

Cited by 10 publications

(7 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent mechanistic studies suggest that the increased protein activity or acquired drug resistance is due to the mutation combinations. Zhang et al 44 suggested that combinations of strong and weak drivers can enhance PI3K activity and explain the phenotypic differences in PIK3CA double mutant tumors 43 that we observed prominently in breast and uterus tumors. Here we further extended the analysis to combinations of less frequent mutations not cataloged as drivers, which we view as potential latent drivers.…”

Section: Discussionsupporting

confidence: 57%

“…One well example of how the co-occurrence of in cis mutations might promote cancer is PI3Kα 29 , 31 . Moreover, crystal structures and experimental research have shown the activation mechanism at the atomic scale, and the role of frequent or rare driver mutations on this mechanism is widely discussed 39 – 43 . E542K, E545K, and H1047R are hotspot helical and kinase domain mutations that can activate PI3Kα, but they can also have additive effects when combined with the moderate mutations E453K/Q, E726K, and M1043V/I 25 , 43 .…”

Section: Resultsmentioning

confidence: 99%

“…The weak mutations cause conformational changes that lead to PI3Kα activation. These weak mutations include E726K and M1043V/I in the kinase domain, N345K, C420R, and E453K/Q in the C2 domain, and R38H/C, R88Q, R93Q, R108H, and G118D in the ABD domain 43 . Thus, the pathological impact of a single driver may be insufficient 44 .…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Pan-cancer clinical impact of latent drivers from double mutations

et al. 2023

Self Cite

View full text Add to dashboard Cite

Here, we discover potential ‘latent driver’ mutations in cancer genomes. Latent drivers have low frequencies and minor observable translational potential. As such, to date they have escaped identification. Their discovery is important, since when paired in cis, latent driver mutations can drive cancer. Our comprehensive statistical analysis of the pan-cancer mutation profiles of ~60,000 tumor sequences from the TCGA and AACR-GENIE cohorts identifies significantly co-occurring potential latent drivers. We observe 155 same gene double mutations of which 140 individual components are cataloged as latent drivers. Evaluation of cell lines and patient-derived xenograft response data to drug treatment indicate that in certain genes double mutations may have a prominent role in increasing oncogenic activity, hence obtaining a better drug response, as in PIK3CA. Taken together, our comprehensive analyses indicate that same-gene double mutations are exceedingly rare phenomena but are a signature for some cancer types, e.g., breast, and lung cancers. The relative rarity of doublets can be explained by the likelihood of strong signals resulting in oncogene-induced senescence, and by doublets consisting of non-identical single residue components populating the background mutational load, thus not identified.

show abstract

Section: Discussionsupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Pan-cancer clinical impact of latent drivers from double mutations

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…All have been linked to the Ras small GTPases superfamily and their signaling components. The activation mechanisms of mutations in cancer have been explored in several proteins, including K-Ras, B-Raf, and PI3Kα ( Lu et al., 2016a , 2016b ; Maloney et al., 2021 ; Nussinov et al., 2021d ; Zhang et al., 2019 ; 2021a ), as well as a comparison between cancer versus neurodevelopmental disorder mutations ( Smith et al., 2019 ). Ongoing work exploiting the recent determination of the activation mechanism of PTEN at the membrane ( Jang et al., 2021 ) aims to elucidate neurodevelopmental mutations in autism versus cancer.…”

Section: The Connections Between Neurodevelopmental Disorders and Cancermentioning

confidence: 99%

Neurodevelopmental disorders, immunity, and cancer are connected

2022

Self Cite

View full text Add to dashboard Cite

“…Drug discovery may similarly benefit from deliberating the protein activation mechanism undertaken by nature. As to the co‐occurrence of double (multiple) cancer driver mutations in cis on the protein target, 4–6 protein conformational behavior suggests that the additive effect of the mutations is unlikely to alter the activation mechanism which would still mimic that of the wild‐type protein 18 . However, the more potent signaling that the multiple mutations abet argues that significant differences in structural details are likely to emerge 7,19 .…”

Section: Introductionmentioning

confidence: 99%

Mechanism of activation and the rewired network: New drug design concepts

Nussinov

Zhang

Maloney

et al. 2021

Medicinal Research Reviews

Self Cite

View full text Add to dashboard Cite

Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism. We suggest that the decision whether to target an inactive (or active) conformation should largely rest on the protein mechanism of activation. We next discuss the recent identification of double (multiple) same‐allele driver mutations and their impact on cell proliferation and suggest that like single driver mutations, double drivers also mimic the mechanism of activation. We further suggest that the structural perturbations of double (multiple) in cis mutations may reveal new surfaces/pockets for drug design. Finally, we underscore the preeminent role of the cellular network which is deregulated in cancer. Our structure‐based review and outlook updates the traditional Mechanism of Action, informs decisions, and calls attention to the intrinsic activation mechanism of the target protein and the rewired tumor‐specific network, ushering innovative considerations in precision medicine.

show abstract

Drugging multiple same-allele driver mutations in cancer

Cited by 10 publications

References 30 publications

Pan-cancer clinical impact of latent drivers from double mutations

Pan-cancer clinical impact of latent drivers from double mutations

Neurodevelopmental disorders, immunity, and cancer are connected

Mechanism of activation and the rewired network: New drug design concepts

Contact Info

Product

Resources

About