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Clinical use of crizotinib for the treatment of non-small cell lung cancer.

Roberts PJ - Biologics (2013)

Bottom Line: Discoveries over the last decade have fundamentally transformed the way we define lung cancer.Gone are the days of the simple binary classification system of non-small cell lung cancer (NSCLC) and small cell lung cancer.This review discusses the clinical development and use of crizotinib in NSCLC.

View Article: PubMed Central - PubMed

Affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

ABSTRACT
Discoveries over the last decade have fundamentally transformed the way we define lung cancer. Gone are the days of the simple binary classification system of non-small cell lung cancer (NSCLC) and small cell lung cancer. Today, accurate identification of the histological and molecular subtype of NSCLC is required for selecting standard cytotoxic chemotherapy and targeted therapies. The identification of anaplastic lymphoma kinase (ALK) rearrangements in 5-7% of NSCLC patients and the rapid clinical development of crizotinib for these patients is the most recent clinical example necessitating the proper identification of the molecular characteristics of NSCLC for treatment decisions. The discovery of ALK rearrangements in NSCLC serendipitously coincided with the development of crizotinib for other ALK or MET driven malignancies. The clinical development of crizotinib for ALK-positive NSCLC patients has been an amazing success story of translational medicine that relied on the prior clinical experience of other targeted predecessors (i.e. erlotinib in EGFR mutant NSCLC) and a compound ready for clinical development to gain expedited FDA approval. This review discusses the clinical development and use of crizotinib in NSCLC.

No MeSH data available.


Related in: MedlinePlus

Aberrant ALK signaling cascade.Notes:ALK gene rearrangements result in aberrant ALK signaling through PI3K/AKT/mTOR, JAK/STAT, and RAS/MEK/ERK signaling pathways. Constitutive ALK signaling mediates enhanced cell proliferation, cell survival, and metabolism. Current efforts to target aberrant ALK signaling in cancer include inhibition with ALK tyrosine kinase inhibitors and inhibition of the molecular chaperone heat shock protein 90, which leads to reduced ALK expression.
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f1-btt-7-091: Aberrant ALK signaling cascade.Notes:ALK gene rearrangements result in aberrant ALK signaling through PI3K/AKT/mTOR, JAK/STAT, and RAS/MEK/ERK signaling pathways. Constitutive ALK signaling mediates enhanced cell proliferation, cell survival, and metabolism. Current efforts to target aberrant ALK signaling in cancer include inhibition with ALK tyrosine kinase inhibitors and inhibition of the molecular chaperone heat shock protein 90, which leads to reduced ALK expression.

Mentions: The ALK gene was originally discovered by cloning a translocation found in a subset of anaplastic large cell lymphomas.10 The presence of ALK rearrangements in NSCLC were first reported in 20077 and are present in 5%–7% of NSCLC patients.11–14 The activated ALK fusion proteins have been shown to drive oncogenic transformation through several molecular signaling pathways,15 including PI3K/AKT/mTOR, JAK/STAT, and RAS/MEK/ERK (Figure 1). The discovery of ALK rearrangements in NSCLC serendipitously coincided with the development of crizotinib for other ALK or MET-driven malignancies,16,17 allowing for expedited clinical development (Figure 2) and ultimately approval by the US Food and Drug Administration (FDA). This review will discuss the clinical development and use of crizotinib in NSCLC.


Clinical use of crizotinib for the treatment of non-small cell lung cancer.

Roberts PJ - Biologics (2013)

Aberrant ALK signaling cascade.Notes:ALK gene rearrangements result in aberrant ALK signaling through PI3K/AKT/mTOR, JAK/STAT, and RAS/MEK/ERK signaling pathways. Constitutive ALK signaling mediates enhanced cell proliferation, cell survival, and metabolism. Current efforts to target aberrant ALK signaling in cancer include inhibition with ALK tyrosine kinase inhibitors and inhibition of the molecular chaperone heat shock protein 90, which leads to reduced ALK expression.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3643289&req=5

f1-btt-7-091: Aberrant ALK signaling cascade.Notes:ALK gene rearrangements result in aberrant ALK signaling through PI3K/AKT/mTOR, JAK/STAT, and RAS/MEK/ERK signaling pathways. Constitutive ALK signaling mediates enhanced cell proliferation, cell survival, and metabolism. Current efforts to target aberrant ALK signaling in cancer include inhibition with ALK tyrosine kinase inhibitors and inhibition of the molecular chaperone heat shock protein 90, which leads to reduced ALK expression.
Mentions: The ALK gene was originally discovered by cloning a translocation found in a subset of anaplastic large cell lymphomas.10 The presence of ALK rearrangements in NSCLC were first reported in 20077 and are present in 5%–7% of NSCLC patients.11–14 The activated ALK fusion proteins have been shown to drive oncogenic transformation through several molecular signaling pathways,15 including PI3K/AKT/mTOR, JAK/STAT, and RAS/MEK/ERK (Figure 1). The discovery of ALK rearrangements in NSCLC serendipitously coincided with the development of crizotinib for other ALK or MET-driven malignancies,16,17 allowing for expedited clinical development (Figure 2) and ultimately approval by the US Food and Drug Administration (FDA). This review will discuss the clinical development and use of crizotinib in NSCLC.

Bottom Line: Discoveries over the last decade have fundamentally transformed the way we define lung cancer.Gone are the days of the simple binary classification system of non-small cell lung cancer (NSCLC) and small cell lung cancer.This review discusses the clinical development and use of crizotinib in NSCLC.

View Article: PubMed Central - PubMed

Affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

ABSTRACT
Discoveries over the last decade have fundamentally transformed the way we define lung cancer. Gone are the days of the simple binary classification system of non-small cell lung cancer (NSCLC) and small cell lung cancer. Today, accurate identification of the histological and molecular subtype of NSCLC is required for selecting standard cytotoxic chemotherapy and targeted therapies. The identification of anaplastic lymphoma kinase (ALK) rearrangements in 5-7% of NSCLC patients and the rapid clinical development of crizotinib for these patients is the most recent clinical example necessitating the proper identification of the molecular characteristics of NSCLC for treatment decisions. The discovery of ALK rearrangements in NSCLC serendipitously coincided with the development of crizotinib for other ALK or MET driven malignancies. The clinical development of crizotinib for ALK-positive NSCLC patients has been an amazing success story of translational medicine that relied on the prior clinical experience of other targeted predecessors (i.e. erlotinib in EGFR mutant NSCLC) and a compound ready for clinical development to gain expedited FDA approval. This review discusses the clinical development and use of crizotinib in NSCLC.

No MeSH data available.


Related in: MedlinePlus