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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...
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BCL-2 Family Inhibition Enhances mTORC1/2 Inhibition in PIK3CA-Mutant Colorectal Cancer.

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Combining MTORC1/2 and BCL-2 family inhibitors shows promise for PIK3CA-mutant colorectal cancers (CRCs). This strategy, including navitoclax, overcomes resistance to PI3K pathway inhibitors in CRC models.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Precision Medicine

Background:

  • Targeting PIK3CA-mutant colorectal cancers (CRCs) is a key precision medicine strategy.
  • Resistance to single-agent PI3K inhibitors necessitates combination therapies.
  • MTORC1/2 inhibition is crucial for response in PIK3CA-mutant CRCs.

Purpose of the Study:

  • To identify combination therapies enhancing copanlisib efficacy in PIK3CA-mutant CRCs.
  • To evaluate navitoclax as a potential sensitizer to PI3K/MTOR inhibitors.
  • To investigate resistance mechanisms and identify key targets for combination therapy.

Main Methods:

  • High-throughput drug screening using Apc and Pik3ca mutant mouse-derived cancer organoids.
  • In vitro and in vivo evaluation of combination therapies (copanlisib, sapanisertib, dactolisib with navitoclax).
  • Analysis of patient-derived cancer organoids with diverse mutation profiles.

Main Results:

  • Navitoclax enhanced PI3K/MTOR inhibition and induced apoptosis in CRC models.
  • KRAS mutations were identified as a potential resistance factor.
  • BCL-xL was identified as the primary BCL-2 family target for this combination therapy.

Conclusions:

  • Combination of MTORC1/2 and BCL-2 family inhibition is a promising strategy for PIK3CA-mutant CRCs.
  • Navitoclax potentiates PI3K/MTOR inhibitors by targeting BCL-xL.
  • Further investigation into KRAS mutation impact on treatment response is warranted.