Related Experiment Video

Updated: Sep 15, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

6.2K

Phosphoinositide 3-kinase regulates wild-type RAS signaling to confer resistance to KRAS inhibition

Xiangyu Ge, Jaffarguriqbal Singh, Wenxue Li

    Biorxiv : the Preprint Server for Biology
    |July 16, 2025
    PubMed

    Insights

    Phosphoinositide 3-kinase (PI3K) drives resistance to KRAS inhibitors in pancreatic cancer by activating wild-type RAS signaling. Inhibiting PI3K enhances sensitivity to KRAS-targeted therapies in PDAC.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Cancer Signaling

    Background:

    • Pancreatic ductal adenocarcinomas (PDAC) heavily rely on KRAS mutations.
    • Resistance to KRAS inhibitors is a significant challenge in PDAC treatment.
    • The precise mechanisms driving KRAS inhibitor resistance are not fully understood.

    Purpose of the Study:

    • To investigate the role of phosphoinositide 3-kinase (PI3K) in mediating resistance to KRAS inhibition in PDAC.
    • To elucidate the signaling pathways through which PI3K contributes to this resistance.
    • To explore the therapeutic potential of combining PI3K and KRAS inhibitors.

    Main Methods:

    • Proximity labeling
    • CRISPR screens
    • Live-cell imaging
    • Functional assays
    • Analysis of RAS signaling complexes

    Main Results:

    • PI3K activates wild-type RAS signaling upstream of KRAS, contributing to resistance.
    • PI3K orchestrates GAB1 recruitment and RAS signaling complex assembly via phosphoinositides.
    • This PI3K-driven signaling activates the MAPK pathway in an EGFR/SHP2/SOS1-dependent manner.
    • PI3K inhibition increases PDAC cell sensitivity to KRAS inhibitors, including in cells with PIK3CA mutations.

    Conclusions:

    • PI3K plays a critical role in KRAS inhibitor resistance in PDAC through novel wild-type RAS activation.
    • Targeting PI3K can overcome resistance mechanisms and enhance the efficacy of KRAS-targeted therapies.
    • These findings offer new strategies for improving PDAC treatment outcomes.

    More Related Videos

    Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases06:56

    Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases

    Published on: September 6, 2024

    468
    Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans08:12

    Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

    Published on: October 5, 2020

    3.1K

    Related Concept Videos

    The Ras Gene02:38

    The Ras Gene

    The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
    Ras is a...
    6.4K
    PI3K/mTOR/AKT Signaling Pathway01:22

    PI3K/mTOR/AKT Signaling Pathway

    The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
    4.0K
    The JAK-STAT Signaling Pathway01:20

    The JAK-STAT Signaling Pathway

    Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
    9.3K
    Small GTPases - Ras and Rho01:24

    Small GTPases - Ras and Rho

    Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
    Three regulatory proteins control their activity:
    4.2K
    Amplifying Signals via Enzymatic Cascade01:22

    Amplifying Signals via Enzymatic Cascade

    When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
    8.9K
    Interactions Between Signaling Pathways01:19

    Interactions Between Signaling Pathways

    Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
    Convergence and divergence, and cross-talk between signaling pathways
    Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
    6.5K