Related Experiment Video

Updated: Jul 18, 2026

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

Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants

Brian J Skaggs1, Mercedes E Gorre, Ann Ryvkin

  • 1Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095, USA.

Proceedings of the National Academy of Sciences of the United States of America
|December 14, 2006
PubMed

Insights

Drug-resistant BCR-ABL mutations in chronic myeloid leukemia can alter kinase function and oncogenicity. The T315I mutation uniquely impacts phosphorylation, affecting disease progression despite ABL inhibitor resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Targeting kinases with small molecule inhibitors is crucial in cancer therapy.
  • Drug-resistant kinase domain mutations, particularly in BCR-ABL, are a major cause of relapse in chronic myeloid leukemia (CML).
  • Some resistance mutations pre-exist treatment, indicating enhanced fitness over wild-type BCR-ABL.

Purpose of the Study:

  • To evaluate the oncogenic potential of eight kinase inhibitor-resistant BCR-ABL mutants.
  • To investigate the impact of the T315I mutation on BCR-ABL function and phosphoproteome.
  • To understand how gatekeeper residue mutations influence oncogenicity through altered phosphorylation.

Main Methods:

  • Assessed oncogenicity of eight BCR-ABL mutants.
  • Performed global phosphoproteome analysis.
  • Conducted mutational analysis of tyrosine residues in the ATP binding loop (P-loop) in the context of Thr315 mutations.

Main Results:

  • A spectrum of oncogenic potencies was observed for the evaluated BCR-ABL mutants.
  • The T315I mutation confers resistance to all approved ABL kinase inhibitors and exhibits unique phosphosubstrate alterations.
  • Specific tyrosine phosphorylation shifts (Tyr253 and Tyr257) in the P-loop were identified for Thr315 gatekeeper mutations (Ile or Ala).

Conclusions:

  • Kinase inhibitor resistance mutations can significantly alter BCR-ABL kinase function and confer novel biological properties.
  • Gatekeeper residue identity critically impacts oncogenicity via modulation of P-loop phosphorylation.
  • These alterations in kinase function and biological properties may influence CML disease progression.

More Related Videos

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence10:09

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence

Published on: January 7, 2019

Related Concept Videos

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 specific...
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 the...
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...
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...
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 superfamily...
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 rapamycin-insensitive companion...