Emerging Trends in Cancer Drug Discovery—From Drugging the “Undruggable” to Overcoming Resistance

Rudolph, Joachim; Settleman, Jeff; Malek, Shiva

doi:10.1158/2159-8290.cd-21-0260

Cited by 29 publications

(25 citation statements)

References 36 publications

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“…The paramount importance of K-RAS mutations in cancer has led to a prolonged effort to develop strategies to target this protein that however was considered to be undruggable due to its structural characteristics. However, the presence of a thiol group at Cys 12 of K-RAS G12C offered an opportunity to develop inhibitors against this specific mutant, which is present with a notable frequency in certain cancer types and specifically in NSCLC (6). Following this strategy, a new family of compounds aimed at targeting K-RAS G12C has been developed.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Mapping of Non-Small Cell Lung Cancer K-RAS p.G12C Mutated Tumors: Identification of Surfaceome Targets and Immunologic Correlates

et al. 2022

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Targeting K-RAS-mutant non-small cell lung cancer (NSCLC) with novel inhibitors has shown promising results with the recent approval of sotorasib in this indication. However, progression to this agent is expected, as it has previously been observed with other inhibitors. Recently, new immune therapeutics, including vectorized compounds with antibodies or modulators of the host immune response, have demonstrated clinical activity. By interrogating massive datasets, including TCGA, we identified genes that code for surface membrane proteins that are selectively expressed in K-RAS mutated NSCLC and that could be used to vectorize novel therapies. Two genes, CLDN10 and TMPRSS6, were selected for their clear differentiation. In addition, we discovered immunologic correlates of outcome that were clearly de-regulated in this particular tumor type and we matched them with immune cell populations. In conclusion, our article describes membrane proteins and immunologic correlates that could be used to better select and optimize current therapies.

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Section: Introductionmentioning

confidence: 99%

Transcriptomic Mapping of Non-Small Cell Lung Cancer K-RAS p.G12C Mutated Tumors: Identification of Surfaceome Targets and Immunologic Correlates

et al. 2022

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“…However, their highly similar catalytic structures make this task almost impossible for traditional inhibitors. Proximity-inducing drugs (Proxidrugs) regulating intracellular degradation of therapeutic targets have emerged as a possible strategy to treat a large number of cancers that have been considered non-treatable to date [130,131]. As USP28 and USP25 only share 51% of their structures [6], it may be possible to identify and characterize suitable ligands that specifically interact with USP28, to develop a novel generation of USP28 Proxidrug inhibitors.…”

Section: Inhibitors Of Usp28 For Scc Cancer Therapy: Progress and Perspectivementioning

confidence: 99%

USP28: Oncogene or Tumor Suppressor? A Unifying Paradigm for Squamous Cell Carcinoma

Prieto-Garcia

Tomašković

Shah

et al. 2021

Cells

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Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: 1) The emerging role of USP28 in cancer. 2) The complexity and mutational landscape of squamous tumors. 3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. 4) The development and current state of novel USP28 inhibitors.

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“…Examples comprise trastuzumab or cetuximab against HER2 or EGFR, or vemurafenib against the BRAF V600 mutated protein [ 4 , 5 ]. Targeting non oncogenic druggable vulnerabilities have also shown clinical efficacy, for example using drugs acting against epigenetic components, or the tumor microenvironment, or when optimizing synthetic lethality interactions, where a classic example is the use of PARP inhibitors in tumors harboring BRCA1/2 mutations [ 6 – 8 ]. Beyond the druggability properties, inhibition of pan essential genes in tumor cells has shown preclinical and clinical activity, since those genes are involved in relevant biological functions, including cell cycle proliferation or transcription, among many other functions.…”

Section: Introductionmentioning

confidence: 99%

“…One of the main limitations in drug development is the fact that most chemical agents act against the enzymatic activity of proteins, with very limited options for targeting oncoproteins without this activity [ 8 , 9 ]. Recently, degradation of targeted proteins using proteolysis targeting chimeras (PROTACs), has gain momentum [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical considerations for the design of PROTACs in cancer

et al. 2022

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Degradation of targeted proteins using proteolysis targeting chimeras (PROTACs) has gained momentum. A PROTAC is a bifunctional molecule that consists of three parts: a ligand that interacts with the protein to be degraded, another ligand that binds to an E3 ubiquitin ligase and a linker that connects both. Identification of the right proteins as targets to be degraded and a ligase that is highly expressed in tumors compare with normal tissue is mandatory, as can augment efficacy reducing toxicity. In this article we review the current development stage of PROTACs in cancer to categorize the best PROTAC construction. Targets including BCL2, CDK4 and MCL1 were highly expressed in all tumors; MCL1 was significantly increased in breast cancer and lung adenocarcinoma and CDK4 in colon adenocarcinoma. Degradation of CDK9, AURKA or PLK1, followed by BCL2, MCL1, PTPN11, BRD4, PTK2, showed a high dependency. Most ligases evaluated were not highly present in tumors except for MDM2 in breast, lung, prostate and gastric cancer. In non-transformed tissue MDM2 was the most abundant ligase, followed by cIAP and CRBN, and those with low expression included XIAP and VHL. MDM2 ligase coupled with inhibitors of the targets BCL2, BRD4, CDK9, PLK1 and MCL1 in stomach tumor, and MDM2 with PIK3C3 inhibitors in breast cancer, seems to be the best therapeutic strategy. Our results suggest potential options for the design of PROTACS in specific medical indications.

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Emerging Trends in Cancer Drug Discovery—From Drugging the “Undruggable” to Overcoming Resistance

Cited by 29 publications

References 36 publications

Transcriptomic Mapping of Non-Small Cell Lung Cancer K-RAS p.G12C Mutated Tumors: Identification of Surfaceome Targets and Immunologic Correlates

Transcriptomic Mapping of Non-Small Cell Lung Cancer K-RAS p.G12C Mutated Tumors: Identification of Surfaceome Targets and Immunologic Correlates

USP28: Oncogene or Tumor Suppressor? A Unifying Paradigm for Squamous Cell Carcinoma

Clinical considerations for the design of PROTACs in cancer

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