bims-pimaco 2024-01-07 papers

bims-pimaco

Biomed News

on PI3K and MAPK signalling in colorectal cancer

Issue of 2024‒01‒07
seven papers selected by
Lucas B. Zeiger, Beatson Institute for Cancer Research

KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo.
A high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Kα.
Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial.
Predictive, preventive, and personalized medicine in breast cancer: targeting the PI3K pathway.
Unraveling the Concealed Transcriptomic Landscape of PTEN in Human Malignancies.
A comprehensive review of small molecules targeting PI3K pathway: Exploring the structural development for the treatment of breast cancer.
Identification of colorectal cancer cell stemness from single-cell RNA sequencing.

Nat Commun. 2024 Jan 02. 15(1): 100

KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo.

Arafath K Najumudeen, Sigrid K Fey, Laura M Millett, Catriona A Ford, Kathryn Gilroy, Nuray Gunduz, Rachel A Ridgway, Eve Anderson, Douglas Strathdee, William Clark, Colin Nixon, Jennifer P Morton, Andrew D Campbell, Owen J Sansom.

Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-type Kras in the context of oncogenic Kras. Deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-type Kras upon tumour initiation, progression and therapeutic response in Kras mutant CRC.

DOI: https://doi.org/10.1038/s41467-023-44342-4
Chem Sci. 2024 Jan 03. 15(2): 683-691

A high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Kα.

Werner Theodor Jauslin, Matthias Schild, Thorsten Schaefer, Chiara Borsari, Clara Orbegozo, Lukas Bissegger, Saule Zhanybekova, Danilo Ritz, Alexander Schmidt, Matthias Wymann, Dennis Gillingham.

Class I phosphoinositide 3-kinases (PI3Ks) control cellular growth, but are also essential in insulin signaling and glucose homeostasis. Pan-PI3K inhibitors thus generate substantial adverse effects, a reality that has plagued drug development against this target class. We present here evidence that a high affinity binding module with the capacity to target all class I PI3K isoforms can facilitate selective degradation of the most frequently mutated class I isoform, PI3Kα, when incorporated into a cereblon-targeted (CRBN) degrader. A systematic proteomics study guided the fine tuning of molecular features to optimize degrader selectivity and potency. Our work resulted in the creation of WJ112-14, a PI3Kα-specific nanomolar degrader that should serve as an important research tool for studying PI3K biology. Given the toxicities observed in the clinic with unselective PI3Kα inhibitors, the results here offer a new approach toward selectively targeting this frequently mutated oncogenic driver.

DOI: https://doi.org/10.1039/d3sc04629j
Nat Med. 2024 Jan 04.

Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial.

Yasutoshi Kuboki, Marwan Fakih, John Strickler, Rona Yaeger, Toshiki Masuishi, Edward J Kim, Christine M Bestvina, Scott Kopetz, Gerald S Falchook, Corey Langer, John Krauss, Sonam Puri, Panli Cardona, Emily Chan, Tracy Varrieur, Lata Mukundan, Abraham Anderson, Qui Tran, David S Hong.

The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg-1, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .

DOI: https://doi.org/10.1038/s41591-023-02717-6
J Transl Med. 2024 Jan 03. 22(1): 15

Predictive, preventive, and personalized medicine in breast cancer: targeting the PI3K pathway.

Muhammad Tufail, Jia-Ju Hu, Jie Liang, Cai-Yun He, Wen-Dong Wan, Yu-Qi Huang, Can-Hua Jiang, Hong Wu, Ning Li.

  Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase (PI3K) pathway has emerged as a crucial contributor to the development, advancement, and resistance to treatment. This review article explores the implications of the PI3K pathway in predictive, preventive, and personalized medicine for BC. It emphasizes the identification of predictive biomarkers, such as PIK3CA mutations, and the utility of molecular profiling in guiding treatment decisions. The review also discusses the potential of targeting the PI3K pathway for preventive strategies and the customization of therapy based on tumor stage, molecular subtypes, and genetic alterations. Overcoming resistance to PI3K inhibitors and exploring combination therapies are addressed as important considerations. While this field holds promise in improving patient outcomes, further research and clinical trials are needed to validate these approaches and translate them into clinical practice.

Keywords:  Breast cancer; PI3K pathway; Personalized medicine; Predictive medicine; Preventive medicine

DOI:  https://doi.org/10.1186/s12967-023-04841-w
Curr Genomics. 2023 Dec 12. 24(4): 250-262

Unraveling the Concealed Transcriptomic Landscape of PTEN in Human Malignancies.

Michaela A Boti, Panagiotis G Adamopoulos, Dido Vassilacopoulou, Andreas Scorilas.

  Background: Phosphatase and tensin homolog, widely known as PTEN, is a major negative regulator of the PI3K/AKT/mTOR signaling pathway, involved in the regulation of a variety of important cellular processes, including cell proliferation, growth, survival, and metabolism. Since most of the molecules involved in this biological pathway have been described as key regulators in cancer, the study of the corresponding genes at several levels is crucial.Objective: Although previous studies have elucidated the physiological role of PTEN under normal conditions and its involvement in carcinogenesis and cancer progression, the transcriptional profile of PTEN has been poorly investigated.
Methods: In this study, instead of conducting the "gold-standard" direct RNA sequencing that fails to detect less abundant novel mRNAs due to the decreased sequencing depth, we designed and implemented a multiplexed PTEN-targeted sequencing approach that combined both short- and long-read sequencing.
Results: Our study has highlighted a broad spectrum of previously unknown PTEN mRNA transcripts and assessed their expression patterns in a wide range of human cancer and non-cancer cell lines, shedding light on the involvement of PTEN in cell cycle dysregulation and thus tumor development.
Conclusion: The identification of the described novel PTEN splice variants could have significant implications for understanding PTEN regulation and function, and provide new insights into PTEN biology, opening new avenues for monitoring PTEN-related diseases, including cancer.

Keywords:  Phosphatase and tensin homolog; alternative splicing; cytogenetic; long-read sequencing; splice variants; tumor suppression

DOI:  https://doi.org/10.2174/0113892029265367231013113304
Bioorg Chem. 2023 Dec 30. pii: S0045-2068(23)00738-1. [Epub ahead of print]143 107077

A comprehensive review of small molecules targeting PI3K pathway: Exploring the structural development for the treatment of breast cancer.

Rahul Dubey, Anushka Sharma, Shankar Gupta, G D Gupta, Vivek Asati.

  Cancer stands as one of the deadliest diseases, ranking second in terms of its global impact. Despite the presence of numerous compelling theories concerning its origins, none have succeeded in fully elucidating the intricate nature of this ailment. Among the prevailing concerns in today's world, breast cancer proliferation remains a significant issue, particularly affecting females. The abnormal proliferation of the PI3K pathway emerges as a prominent driver of breast cancer, underscoring its role in cellular survival and proliferation. Consequently, targeting this pathway has emerged as a leading strategy in breast cancer therapeutics. Within this context, the present article explores the current landscape of anti-tumour drug development, focusing on structural activity relationships (SAR) in PI3K targeting breast cancer treatment. Notably, certain moieties like triazines, pyrimidine, quinazoline, quinoline, and pyridoxine have been explored as potential PI3K inhibitors for combating breast cancer. Various heterocyclic small molecules are undergoing clinical trials, such as Alpelisib, the first orally available FDA-approved drug targeting PI3K; others include buparlisib, pictilisib, and taselisib, which inhibit class I PI3K. These drugs are used for the treatment of breast cancer but still have various side effects with their high cost. Therefore, the primary goal of this review is to include all current advances in the development of anticancer medicines that target PI3K over-activation in the treatment of breast cancer.

Keywords:  Angiogenesis; Antitumor; Breast cancer; Clinical trials drugs; NCT; PI3K

DOI:  https://doi.org/10.1016/j.bioorg.2023.107077
Mol Cancer Res. 2023 Dec 29.

Identification of colorectal cancer cell stemness from single-cell RNA sequencing.

Kangyu Lin, Saikat Chowdhury, Mohammad A Zeineddine, Fadl A Zeineddine, Nicholas J Hornstein, Oscar E Villarreal, Dipen M Maru, Cara L Haymaker, Jean-Nicolas Vauthey, George J Chang, Elena Bogatenkova, David Menter, Scott Kopetz, John Paul Shen.

Cancer stem cells (CSCs) play a critical role in metastasis, relapse, and therapy resistance in colorectal cancer. While characterization of the normal lineage of cell development in the intestine has led to the identification of many genes involved in the induction and maintenance of pluripotency, recent studies suggest significant heterogeneity in CSC populations. Moreover, while many canonical colorectal cancer CSC marker genes have been identified, the ability to use these classical markers to annotate stemness at the single-cell level is limited. In this study, we performed single-cell RNA sequencing on a cohort of 6 primary colon, 9 liver metastatic tumors, and 11 normal (non-tumor) controls to identify colorectal CSCs at the single-cell level. Finding poor alignment of the 11 genes most used to identify colorectal CSC, we instead extracted a single-cell stemness signature (SCS_sig) that robustly identified 'gold-standard' colorectal CSCs that expressed all marker genes. Using this SCS_sig to quantify stemness, we found that while normal epithelial cells show a bimodal distribution, indicating distinct stem and differentiated states, in tumor epithelial cells stemness is a continuum, suggesting greater plasticity in these cells. The SCS_sig score was quite variable between different tumors, reflective of the known transcriptomic heterogeneity of CRC. Notably, patients with higher SCS_sig scores had significantly shorter disease-free survival time after curative intent surgical resection, suggesting stemness is associated with relapse. Implications: This study reveals significant heterogeneity of expression of genes commonly used to identify colorectal CSCs, and identifies a novel stemness signature to identify these cells from scRNAseq data.

DOI: https://doi.org/10.1158/1541-7786.MCR-23-0468