bims-pimaco 2023-02-12 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2023–02–12
ten papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

Combined KRAS G12C and SOS1 inhibition enhances and extends the anti-tumor response in KRAS G12C -driven cancers by addressing intrinsic and acquired resistance.
ATP-competitive and allosteric inhibitors induce differential conformational changes at the autoinhibitory interface of Akt1.
PI(3,5)P 2 Controls the Signaling Activity of Class I PI3K.
Targeting Class I-II-III PI3Ks in Cancer Therapy: Recent Advances in Tumor Biology and Preclinical Research.
Developing SHP2-based combination therapy for KRAS-amplified cancer.
Adagrasib: First Approval.
Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy.
How PTEN mutations degrade function at the membrane and life expectancy of carriers of mutations in the human brain.
Development and safety of PI3K inhibitors in cancer.
ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated BRAFV600E-Mutant Metastatic Colorectal Cancer.

bioRxiv. 2023 Jan 23. pii: 2023.01.23.525210. [Epub ahead of print]

Combined KRAS G12C and SOS1 inhibition enhances and extends the anti-tumor response in KRAS G12C -driven cancers by addressing intrinsic and acquired resistance.

Venu Thatikonda, Hengyu Lu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Simone Lieb, Astrid Jeschko, Annette A Machado, Ethan D Marszalek, Mikhila Mahendra, Philipp A Jaeger, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene Waizenegger, Marco H Hofmann.

Efforts to improve the anti-tumor response to KRAS G12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRAS G12C inhibitor (KRAS G12C i) to those induced by KRAS G12C i alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRAS G12C i induces an anti-tumor response stronger than that observed with KRAS G12C i alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRAS G12C i treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRAS G12C i-resistant CRC models. Our findings position KRAS G12C plus SOS1 inhibition therapy as a promising strategy for treating both KRAS G12C -mutated tumors as well as for addressing acquired resistance to KRAS G12C i.

DOI: https://doi.org/10.1101/2023.01.23.525210
Structure. 2023 Jan 30. pii: S0969-2126(23)00009-6. [Epub ahead of print]

ATP-competitive and allosteric inhibitors induce differential conformational changes at the autoinhibitory interface of Akt1.

Alexandria L Shaw, Matthew A H Parson, Linda Truebestein, Meredith L Jenkins, Thomas A Leonard, John E Burke.

  Akt is a master regulator of pro-growth signaling in the cell. Akt is activated by phosphoinositides that disrupt the autoinhibitory interface between the kinase and pleckstrin homology (PH) domains and then is phosphorylated at T308 and S473. Akt hyperactivation is oncogenic, which has spurred development of potent and selective inhibitors as therapeutics. Using hydrogen deuterium exchange mass spectrometry (HDX-MS), we interrogated the conformational changes upon binding Akt ATP-competitive and allosteric inhibitors. We compared inhibitors against three different states of Akt1. The allosteric inhibitor caused substantive conformational changes and restricts membrane binding. ATP-competitive inhibitors caused extensive allosteric conformational changes, altering the autoinhibitory interface and leading to increased membrane binding, suggesting that the PH domain is more accessible for membrane binding. This work provides unique insight into the autoinhibitory conformation of the PH and kinase domain and conformational changes induced by Akt inhibitors and has important implications for the design of Akt targeted therapeutics.

Keywords:  ATP-competitive inhibitors; Akt; Akt1; HDX-MS; PKB; allosteric inhibitor; allostery; hydrogen exchange; protein kinase

DOI:  https://doi.org/10.1016/j.str.2023.01.007
bioRxiv. 2023 Jan 25. pii: 2023.01.25.525550. [Epub ahead of print]

PI(3,5)P 2 Controls the Signaling Activity of Class I PI3K.

Jiachen Sun, Seohyeon Song, Indira Singaram, Ashutosh Sharma, Wei Wang, Yusi Hu, Wen-Ting Lo, Philipp Alexander Koch, Jean J Zhao, Volker Haucke, Ruixuan Gao, Wonhwa Cho.

3'-Phosphoinositides are ubiquitous cellular lipids that play pivotal regulatory roles in health and disease. Generation of 3'-phosphoinositides are driven by three families of phosphoinositide 3-kinases (PI3K) but the mechanisms underlying their regulation and cross-talk are not fully understood. Among 3'-phosphoinositides, phosphatidylinositol-3,5-bisphosphate (PI(3,5)P 2 ) remains the least understood species in terms of its spatiotemporal dynamics and physiological function due to the lack of specific probes. By means of spatiotemporally resolved in situ quantitative imaging of PI(3,5)P 2 using a newly developed ratiometric PI(3,5)P 2 sensor we demonstrate that a special pool of PI(3,5)P 2 is generated on lysosomes and late endosomes in response to growth factor stimulation. This PI(3,5)P 2 pool, the formation of which is mediated by Class II PI3KC2β and PIKFyve, plays a crucial role in terminating the activity of growth factor-stimulated Class I PI3K, one of the most frequently mutated proteins in cancer, via specific interaction with its regulatory p85 subunit. Cancer-causing mutations of Class I PI3K inhibit the p85-PI(3,5)P 2 interaction and thereby induce sustained activation of Class I PI3K. Our results unravel a hitherto unknown tight regulatory interplay between Class I and II PI3Ks mediated by PI(3,5)P 2 , which may be important for controlling the strength of PI3K-mediated growth factor signaling. These results also suggest a new therapeutic possibility of treating cancer patients with p85 mutations.

DOI: https://doi.org/10.1101/2023.01.25.525550
Cancers (Basel). 2023 Jan 27. pii: 784. [Epub ahead of print]15(3):

Targeting Class I-II-III PI3Ks in Cancer Therapy: Recent Advances in Tumor Biology and Preclinical Research.

Benoît Thibault, Fernanda Ramos-Delgado, Julie Guillermet-Guibert.

  Phosphatidylinositol-3-kinase (PI3K) enzymes, producing signaling phosphoinositides at plasma and intracellular membranes, are key in intracellular signaling and vesicular trafficking pathways. PI3K is a family of eight enzymes divided into three classes with various functions in physiology and largely deregulated in cancer. Here, we will review the recent evidence obtained during the last 5 years on the roles of PI3K class I, II and III isoforms in tumor biology and on the anti-tumoral action of PI3K inhibitors in preclinical cancer models. The dependency of tumors to PI3K isoforms is dictated by both genetics and context (e.g., the microenvironment). The understanding of class II/III isoforms in cancer development and progression remains scarce. Nonetheless, the limited available data are consistent and reveal that there is an interdependency between the pathways controlled by all PI3K class members in their role to promote cancer cell proliferation, survival, growth, migration and metabolism. It is unknown whether this feature contributes to partial treatment failure with isoform-selective PI3K inhibitors. Hence, a better understanding of class II/III functions to efficiently inhibit their positive and negative interactions with class I PI3Ks is needed. This research will provide the proof-of-concept to develop combination treatment strategies targeting several PI3K isoforms simultaneously.

Keywords:  PI3K; cancer; cell signaling; combi/hybrid molecules; combination therapeutics

DOI:  https://doi.org/10.3390/cancers15030784
JCI Insight. 2023 Feb 08. pii: e152714. [Epub ahead of print]8(3):

Developing SHP2-based combination therapy for KRAS-amplified cancer.

Tianxia Li, Osamu Kikuchi, Jin Zhou, Yichen Wang, Babita Pokharel, Klavdija Bastl, Prafulla Gokhale, Aine Knott, Yanxi Zhang, John G Doench, Zandra V Ho, Daniel Vt Catenacci, Adam J Bass.

  Gastroesophageal adenocarcinomas (GEAs) harbor recurrent amplification of KRAS, leading to marked overexpression of WT KRAS protein. We previously demonstrated that SHP2 phosphatase, which acts to promote KRAS and downstream MAPK pathway activation, is a target in these tumors when combined with MEK inhibition. We hypothesized that SHP2 inhibitors may serve as a foundation for developing novel combination inhibitor strategies for therapy of KRAS-amplified GEA, including with targets outside the MAPK pathway. Here, we explore potential targets to effectively augment the efficacy of SHP2 inhibition, starting with genome-wide CRISPR screens in KRAS-amplified GEA cell lines with and without SHP2 inhibition. We identify candidate targets within the MAPK pathway and among upstream RTKs that may enhance SHP2 efficacy in KRAS-amplified GEA. Additional in vitro and in vivo experiments demonstrated the potent cytotoxicity of pan-ERBB kinase inhibitions in vitro and in vivo. Furthermore, beyond targets within the MAPK pathway, we demonstrate that inhibition of CDK4/6 combines potently with SHP2 inhibition in KRAS-amplified GEA, with greater efficacy of this combination in KRAS-amplified, compared with KRAS-mutant, tumors. These results suggest therapeutic combinations for clinical study in KRAS-amplified GEAs.

Keywords:  Drug therapy; Oncogenes; Oncology; Signal transduction

DOI:  https://doi.org/10.1172/jci.insight.152714
Drugs. 2023 Feb 10.

Adagrasib: First Approval.

Sohita Dhillon.

Adagrasib (KRAZATI™) is an orally available, potent, irreversible, small molecule inhibitor of KRAS G12C mutant isoform being developed by Mirati Therapeutics for the treatment of solid tumours harbouring KRAS G12C oncogenic driver mutation, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Adagrasib covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state, thereby preventing downstream signalling without affecting wild-type KRAS protein. In December 2022, adagrasib received its first approval in the USA for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic NSCLC (as determined by an FDA approved test) who have received ≥ 1 prior systemic therapy. It was approved under accelerated approval based on objective response rate and duration of response, and its continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s). The drug is under regulatory review for NSCLC in the European Union and is in development for CRC in the US. Clinical studies of adagrasib in solid tumours, including CRC, are underway in several countries. This article summarizes the milestones in the development of adagrasib leading to this first approval for KRAS G12C-mutated locally advanced or metastatic NSCLC.

DOI: https://doi.org/10.1007/s40265-023-01839-y
Cancers (Basel). 2023 Jan 23. pii: 703. [Epub ahead of print]15(3):

Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy.

Marianna Sirico, Alberto D'Angelo, Caterina Gianni, Chiara Casadei, Filippo Merloni, Ugo De Giorgi.

  The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of the rapamycin (mTOR) axis is a key signal transduction system that links oncogenes and multiple receptor classes which are involved in many essential cellular functions. Aberrant PI3K signalling is one of the most commonly mutated pathways in cancer. Consequently, more than 40 compounds targeting key components of this signalling network have been tested in clinical trials among various types of cancer. As the oncogenic activation of the PI3K/AKT/mTOR pathway often occurs alongside mutations in other signalling networks, combination therapy should be considered. In this review, we highlight recent advances in the knowledge of the PI3K pathway and discuss the current state and future challenges of targeting this pathway in clinical practice.

Keywords:  PI3K inhibitors; clinical trial; mutations; target therapy

DOI:  https://doi.org/10.3390/cancers15030703
bioRxiv. 2023 Jan 27. pii: 2023.01.26.525746. [Epub ahead of print]

How PTEN mutations degrade function at the membrane and life expectancy of carriers of mutations in the human brain.

Hyunbum Jang, Jiaye Chen, Lilia M Iakoucheva, Ruth Nussinov.

PTEN dysfunction, caused by loss of lipid phosphatase activity or deletion, promotes pathologies, cancer, benign tumors, and neurodevelopmental disorders (NDDs). Despite efforts, exactly how the mutations trigger distinct phenotypic outcomes, cancer or NDD, has been puzzling. It has also been unclear how to distinguish between mutations harbored by isoforms, are they cancer or NDDs-related. Here we address both. We demonstrate that PTEN mutations differentially allosterically bias P-loop dynamics and its connection to the catalytic site, affecting catalytic activity. NDD-related mutations are likely to sample conformations present in the wild-type, while sampled conformations sheltering cancer-related hotspots favor catalysis-prone conformations, suggesting that NDD mutations are weaker. Analysis of isoform expression data indicates that if the transcript has NDD-related mutations, alone or in combination with cancer hotspots, there is high prenatal expression. If no mutations within the measured days, low expression levels. Cancer mutations promote stronger signaling and cell proliferation; NDDsâ€™ are weaker, influencing brain cell differentiation. Further, exon 5 is impacted by NDD or non-NDD mutations, while exon 7 is exclusively impacted by NDD mutations. Our comprehensive conformational and genomic analysis helps discover how same allele mutations can foster different clinical manifestations and uncovers correlations of splicing isoform expression to life expectancy.

DOI: https://doi.org/10.1101/2023.01.26.525746
Arch Toxicol. 2023 Feb 11.

Development and safety of PI3K inhibitors in cancer.

Miaomiao Yu, Jiajia Chen, Zhifei Xu, Bo Yang, Qiaojun He, Peihua Luo, Hao Yan, Xiaochun Yang.

  The phosphatidylinositol 3-kinase (PI3K) signalling pathway regulates cell survival, proliferation, migration, metabolism and other vital cellular life processes. In addition, activation of the PI3K signalling pathway is important for cancer development. As a result, a variety of PI3K inhibitors have been clinically developed to treat malignancies. Although several PI3K inhibitors have received approval from the Food and Drug Administration (FDA) for significant antitumour activity, frequent and severe adverse effects have greatly limited their clinical application. These toxicities are mostly on-target and immune-mediated; nevertheless, the underlying mechanisms are still unclear. Current management usually involves intervention through symptomatic treatment, with discontinuation if toxicity persists. Therefore, it is necessary to comprehensively understand these adverse events and ensure the clinical safety application of PI3K inhibitors by establishing the most effective management guidelines, appropriate intermittent dosing regimens and new combination administration. Here, the focus is on the development of PI3K inhibitors in cancer therapy, with particular emphasis on isoform-specific PI3K inhibitors. The most common adverse effects of PI3K inhibitors are also covered, as well as potential mechanisms and management approaches.

Keywords:  Inhibitors; Management; Mechanism; PI3K; Toxicity

DOI:  https://doi.org/10.1007/s00204-023-03440-4
J Clin Oncol. 2023 Feb 10. JCO2201693

ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated BRAFV600E-Mutant Metastatic Colorectal Cancer.

Eric Van Cutsem, Julien Taieb, Rona Yaeger, Takayuki Yoshino, Axel Grothey, Evaristo Maiello, Elena Elez, Jeroen Dekervel, Paul Ross, Ana Ruiz-Casado, Janet Graham, Takeshi Kato, Jose C Ruffinelli, Thierry André, Edith Carrière Roussel, Isabelle Klauck, Mélanie Groc, Jean-Claude Vedovato, Josep Tabernero.

PURPOSE: The positive BEACON colorectal cancer (CRC) safety lead-in, evaluating encorafenib + cetuximab + binimetinib in previously treated patients with BRAFV600E-mutated metastatic CRC (mCRC), prompted the design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier: NCT03693170). ANCHOR CRC aimed to evaluate efficacy, safety, and quality of life with first-line encorafenib + binimetinib + cetuximab in BRAFV600E-mutated mCRC.
METHODS: In this multicenter, open-label, single-arm study, patients with BRAFV600E-mutated mCRC received oral encorafenib 300 mg once daily and binimetinib 45 mg twice daily in 28-day cycles, plus intravenous cetuximab 400 mg/m2 once on Day 1 of Cycle 1, then 250 mg/m2 once weekly for the first seven cycles, and 500 mg/m2 once on Days 1 and 15 from Cycle 8 onward. The primary end point was locally assessed confirmed objective response rate (cORR), and secondary end points included centrally assessed cORR, progression-free survival, overall survival (OS), quality of life, and safety and tolerability.
RESULTS: Among 95 patients, the locally assessed cORR was 47.4% (95% CI, 37.0 to 57.9) with all partial responses. Since the lower limit of the 95% CI exceeded 30%, the primary end point was met. With a median follow-up duration of 20.1 months, the median progression-free survival on the basis of local assessments was 5.8 months and the median OS was 18.3 months. Treatment was well tolerated, with no unexpected toxicities. Using Patient Global Impression of Changes, substantial improvement in symptoms was consistently reported in ≥ 30% of patients from Cycle 3 to Cycle 10.
CONCLUSION: The ANCHOR CRC study showed that the scientifically driven combination of encorafenib + binimetinib + cetuximab was active in the first-line setting of BRAFV600E-mutated mCRC with a manageable safety profile. Further first-line evaluation is ongoing (ClinicalTrails.gov identifier: NCT04607421).

DOI: https://doi.org/10.1200/JCO.22.01693