Related Experiment Video

Updated: Nov 9, 2025

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

15.0K

Mechanisms of KRAS Inhibitor Resistance Revealed

    Cancer Discovery
    |April 15, 2021
    PubMed

    Insights

    Acquired resistance to KRAS G12C inhibitors in non-small cell lung and colorectal cancers arises from diverse mechanisms. These include secondary KRAS mutations, MAPK pathway alterations, and genomic rearrangements, often occurring together.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Genetics

    Background:

    • KRAS G12C mutations are key drivers in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).
    • Targeted KRAS G12C inhibitors have shown promise but acquired resistance limits long-term efficacy.
    • Understanding resistance mechanisms is crucial for improving patient outcomes.

    Purpose of the Study:

    • To investigate the diverse mechanisms of acquired resistance to KRAS G12C inhibitors.
    • To identify specific genetic alterations driving resistance in NSCLC and CRC patients.

    Main Methods:

    • Analysis of patient samples with acquired resistance to KRAS G12C inhibitors.
    • Genomic profiling to detect secondary mutations, pathway alterations, and rearrangements.

    Main Results:

    • Diverse resistance mechanisms were identified, including secondary KRAS mutations.
    • MAPK pathway alterations were observed as a significant resistance mechanism.
    • Genomic rearrangements also contributed to acquired resistance.
    • Multiple resistance mechanisms were found to co-occur in some patients.

    Conclusions:

    • Acquired resistance to KRAS G12C inhibitors is multifactorial.
    • Targeting these diverse resistance pathways may overcome treatment limitations.
    • Further research is needed to develop combination therapies for sustained response.

    More Related Videos

    Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein07:08

    Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein

    Published on: January 16, 2020

    5.9K
    Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer06:51

    Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

    Published on: July 21, 2018

    18.2K

    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...
    6.7K
    Treatment Resistant Cancers02:56

    Treatment Resistant Cancers

    Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
    3.5K
    Inhibition of Cdk Activity02:34

    Inhibition of Cdk Activity

    The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
    5.2K
    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:
    4.6K
    mTOR Signaling and Cancer Progression03:03

    mTOR Signaling and Cancer Progression

    The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
    The mTOR pathway or the...
    4.0K
    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...
    4.4K