Related Experiment Video

Updated: Jul 10, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

6.2K

Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and

Bogdan Popescu1, Carlos Stahlhut2, Theodore C Tarver3

  • 1Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.

Cell Reports. Medicine
|November 22, 2023
PubMed

Insights

Targeting SHP2 and BCL2 shows promise for acute myeloid leukemia (AML) with FLT3/KIT mutations. Co-inhibition overcomes resistance to FLT3 inhibitors by increasing apoptotic dependency on BCL2.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Mutations in receptor tyrosine kinases (RTKs) like FLT3 and KIT are common in acute myeloid leukemia (AML) and linked to poor prognosis.
  • Resistance to FLT3 inhibitors (FLT3i) often involves RAS/MAPK pathway activation, limiting treatment efficacy.

Purpose of the Study:

  • To investigate the pre-clinical efficacy of co-targeting SHP2 and BCL2 in RTK-driven AML.
  • To explore the mechanistic basis for synergistic lethality between SHP2 inhibition and BCL2 inhibition.

Main Methods:

  • Utilized an allosteric SHP2 inhibitor (RMC-4550) and venetoclax (BCL2 inhibitor).
  • Assessed proliferation and apoptosis in AML cell lines with FLT3/KIT mutations, including resistant models.
  • Evaluated drug synergy in cell lines and in vivo xenograft models.

Main Results:

  • RMC-4550 inhibited proliferation in AML cell lines with FLT3 and KIT mutations, including FLT3i-resistant lines.
  • SHP2 inhibition increased apoptotic dependency on BCL2 through MAPK-dependent modulation of BMF and MCL1.
  • RMC-4550 and venetoclax demonstrated synergistic lethality in AML models.

Conclusions:

  • Pharmacologic SHP2 inhibition represents a viable strategy to overcome resistance in RTK-driven AML.
  • Co-targeting SHP2 and BCL2 offers a potent therapeutic approach for FLT3/KIT-mutated AML.
  • Pre-clinical data support the clinical investigation of combined SHP2 and BCL2 inhibition in AML.
Keywords:
FLT3SHP2acute myeloid leukemiaapoptosiscancerdrug synergytargeted therapies

More Related Videos

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:39

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

120
Identifying Protein-protein Interaction Sites Using Peptide Arrays07:44

Identifying Protein-protein Interaction Sites Using Peptide Arrays

Published on: November 18, 2014

18.0K

Related Concept Videos

Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
4.9K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.6K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.7K
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...
6.3K
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
6.4K
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...
8.9K