bims-pimaco 2022-05-22 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2022–05–22
seven papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

Cell line models for drug discovery in PIK3CA-mutated colorectal cancers.
mTOR substrate phosphorylation in growth control.
Emerging RAS-directed therapies for cancer.
RHOA takes the RHOad less traveled to cancer.
Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1.
Emerging actionable targets to treat therapy-resistant colorectal cancers.
Mutational landscape of normal epithelial cells in Lynch Syndrome patients.

Med Oncol. 2022 May 15. 39(5): 89

Cell line models for drug discovery in PIK3CA-mutated colorectal cancers.

Ioannis A Voutsadakis.

  Colorectal cancer remains a major cause of cancer-related morbidity and mortality. Metastatic disease is still incurable in most cases. New therapies based on a better understanding of the pathogenesis are needed to improve outcomes. Mutations in the catalytic sub-unit of kinase PI3K encoded by gene PIK3CA are common in colorectal cancer cell lines and patient samples. The characteristics of colorectal cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE), with and without PIK3CA mutations, were evaluated and compared. A panel of colorectal cancer cell lines with and without PIK3CA mutations were compared for their sensitivity to PIK3 inhibitors. Concomitant molecular abnormalities of sensitive versus resistant cell lines were identified. Colorectal cancer cell lines with PIK3CA mutations are commonly diploid and have microsatellite instability (MSI) and a high tumor mutation burden (TMB), compared with cell lines without PIK3CA mutations. Cell lines with PIK3CA mutations tend to have higher sensitivity to some but not all PI3K inhibitors tested and display variability in sensitivity. Both cell lines with MSI and microsatellite stable (MSS) are among the most sensitive to PI3K inhibitors. Multiple concomitant mutations in the PI3K/AKT and KRAS/BRAF/MEK/ERK pathways are often observed in sensitive cell lines. In concordance with patient samples, colorectal cancer cell lines with PIK3CA mutations display more commonly MSI and tend to be more sensitive to PI3K inhibitors. Variability in sensitivity of PIK3CA-mutated cell lines suggests that additional molecular abnormalities contribute to sensitivity.

Keywords:  CCLE; Drug development; GDSC; PI3K; Targeted therapies

DOI:  https://doi.org/10.1007/s12032-022-01695-y
Cell. 2022 May 12. pii: S0092-8674(22)00460-3. [Epub ahead of print]

mTOR substrate phosphorylation in growth control.

Stefania Battaglioni, Don Benjamin, Matthias Wälchli, Timm Maier, Michael N Hall.

The target of rapamycin (TOR), discovered 30 years ago, is a highly conserved serine/threonine protein kinase that plays a central role in regulating cell growth and metabolism. It is activated by nutrients, growth factors, and cellular energy. TOR forms two structurally and functionally distinct complexes, TORC1 and TORC2. TOR signaling activates cell growth, defined as an increase in biomass, by stimulating anabolic metabolism while inhibiting catabolic processes. With emphasis on mammalian TOR (mTOR), we comprehensively reviewed the literature and identified all reported direct substrates. In the context of recent structural information, we discuss how mTORC1 and mTORC2, despite having a common catalytic subunit, phosphorylate distinct substrates. We conclude that the two complexes recruit different substrates to phosphorylate a common, minimal motif.

DOI: https://doi.org/10.1016/j.cell.2022.04.013
Cancer Drug Resist. 2021 ;4(3): 543-558

Emerging RAS-directed therapies for cancer.

Michael Conroy, Darren Cowzer, Walter Kolch, Austin G Duffy.

  RAS oncogenes are the most commonly mutated oncogenes in human cancer, and RAS-mutant cancers represent a major burden of human disease. Though these oncogenes were discovered decades ago, recent years have seen major advances in understanding of their structure and function, including the therapeutic and prognostic significance of diverse isoforms. Targeting of these mutations has proven difficult, despite some successes with inhibition of RAS effector signalling. More recently, direct RAS inhibition has been achieved in a trial setting. While this has yet to be translated to everyday clinical practice, this development carries much promise. This review summarizes the diverse approaches that have been taken to RAS inhibition and then focuses on the most recent developments in direct inhibition of KRAS(G12C).

Keywords:  Ras; erk; inhibition; isoform; pancreatic; signalling; targeted

DOI:  https://doi.org/10.20517/cdr.2021.07
Trends Cancer. 2022 May 11. pii: S2405-8033(22)00092-9. [Epub ahead of print]

RHOA takes the RHOad less traveled to cancer.

Antje Schaefer, Channing J Der.

  RAS and RHO GTPases function as signaling nodes that regulate diverse cellular processes. Whereas RAS mutations were identified in human cancers nearly four decades ago, only recently have mutations in two RHO GTPases, RAC1 and RHOA, been identified in cancer. RAS mutations are found in a diverse spectrum of human cancer types. By contrast, RAC1 and RHOA mutations are associated with distinct and restricted cancer types. Despite a conservation of RAS and RAC1 residues that comprise mutational hotspots, RHOA mutations comprise highly divergent hotspots. Whereas RAS and RAC1 act as oncogenes, RHOA may act as both an oncogene and a tumor suppressor. Thus, while RAS and RHO each take different mutational paths, they arrive at the same biological destination as cancer drivers.

Keywords:  RAC1; RAS; RHOA; gastric cancer; lymphoma

DOI:  https://doi.org/10.1016/j.trecan.2022.04.005
J Biol Chem. 2022 May 13. pii: S0021-9258(22)00470-7. [Epub ahead of print] 102030

Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1.

Gwen R Buel, Huy Dang, John M Asara, John Blenis, Anders P Mutvei.

The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine kinase complex that promotes anabolic processes including protein, lipid, and nucleotide synthesis, while suppressing catabolic processes such as macroautophagy. mTORC1 activity is regulated by growth factors and amino acids which signal through distinct but integrated molecular pathways: growth factors largely signal through the PI3K/Akt-dependent pathway, whereas the availabilities of amino acids leucine and arginine are communicated to mTORC1 by the Rag-GTPase pathway. While it is relatively well described how acute changes in leucine and arginine levels affect mTORC1 signaling, the effects of prolonged amino acid deprivation remain less well understood. Here, we demonstrate that prolonged deprivation of arginine and/or leucine leads to reactivation of mTORC1 activity, which reaches activation levels similar to those observed in nutrient-rich conditions. Surprisingly, we find that this reactivation is independent of the regeneration of amino acids by canonical autophagy or proteasomal degradation, but is dependent on PI3K/Akt signaling. Together, our data identify a novel crosstalk between the amino acid and PI3K/Akt signaling pathways upstream of mTORC1. These observations extend our understanding of the role of mTORC1 in growth-related diseases and indicate that dietary intervention by removal of leucine and/or arginine may be an ineffective therapeutic approach.

DOI: https://doi.org/10.1016/j.jbc.2022.102030
Cancer Drug Resist. 2022 ;5(1): 36-63

Emerging actionable targets to treat therapy-resistant colorectal cancers.

Emanuela Grassilli, Maria Grazia Cerrito.

  In the last two decades major improvements have been reached in the early diagnosis of colorectal cancer (CRC) and, besides chemotherapy, an ampler choice of therapeutic approaches is now available, including targeted and immunotherapy. Despite that, CRC remains a "big killer" mainly due to the development of resistance to therapies, especially when the disease is diagnosed after it is already metastatic. At the same time, our knowledge of the mechanisms underlying resistance has been rapidly expanding which allows the development of novel therapeutic options in order to overcome it. As far as resistance to chemotherapy is concerned, several contributors have been identified such as: intake/efflux systems upregulation; alterations in the DNA damage response, due to defect in the DNA checkpoint and repair systems; dysregulation of the expression of apoptotic/anti-apoptotic members of the BCL2 family; overexpression of oncogenic kinases; the presence of cancer stem cells; and the composition of the tumoral microenvironment and that of the gut microbiota. Interestingly, several mechanisms are also involved in the resistance to targeted and/or immunotherapy. For example, overexpression and/or hyperactivation and/or amplification of oncogenic kinases can sustain resistance to targeted therapy whereas the composition of the gut microbiota, as well as that of the tumoral niche, and defects in DNA repair systems are crucial for determining the response to immunotherapy. In this review we will make an overview of the main resistance mechanisms identified so far and of the new therapeutic approaches to overcome it.

Keywords:  BRAF; Colorectal cancer; EGFR; ERBB2; MET; chemotherapy; gut microbiota; immune checkpoint inhibitors; kinase inhibitors; resistance; target therapy

DOI:  https://doi.org/10.20517/cdr.2021.96
Nat Commun. 2022 May 17. 13(1): 2710

Mutational landscape of normal epithelial cells in Lynch Syndrome patients.

Bernard C H Lee, Philip S Robinson, Tim H H Coorens, Helen H N Yan, Sigurgeir Olafsson, Henry Lee-Six, Mathijs A Sanders, Hoi Cheong Siu, James Hewinson, Sarah S K Yue, Wai Yin Tsui, Annie S Y Chan, Anthony K W Chan, Siu Lun Ho, Peter J Campbell, Inigo Martincorena, Simon J A Buczacki, Siu Tsan Yuen, Suet Yi Leung, Michael R Stratton.

Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes.

DOI: https://doi.org/10.1038/s41467-022-29920-2