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Current Applications for Overcoming Resistance to Targeted Therapies pp 1–33Cite as

Introduction to the Acquisition of Resistance to Targeted Therapy

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Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 20))

Abstract

The complex process of cancer development and tumorigenesis involves several critical events that take place concurrently or build upon each other, ultimately manifesting as a malignancy with therapeutically targetable components. Given the broad and unspecific cytotoxic effects of chemotherapy, supplementing conventional therapeutic options with targeted therapies initially showed promise in the clinic, particularly in cases where oncogenic addiction (i.e. the dependence on one pathway to maintain tumorigenesis) was a factor. A combination of one or more of these targeted therapeutic options has also shown promise. However, the underlying challenge of treating cancer is its uncanny ability to seamlessly adapt and resist the therapeutic effects of these targeted agents, rendering them ineffective. Other mechanisms can include relying on alternative pathways to sustain their growth. This introduction provides a comprehensive overview of the mechanisms of acquired resistance as they pertain to targeted therapies and indicate in which chapters specific topics will be addressed in more detail. Collectively, this book aims to provide current advancements in the therapeutic arms race between cancer and clinicians and scientists alike to overcome resistance to targeted therapies. We provide a comprehensive overview of the challenges and solutions to resistance to several conventional targeted therapies in addition to providing a discussion on broad topics including targeting components of the tumor microenvironment, emerging therapeutic options, and novel areas to be explored concerning nanotechnology and the epigenome.

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Notes

  1. 1.

    MYC is a proto-oncogene that regulates cell proliferation and growth.

  2. 2.

    Bcl-2 is a family of proteins that regulate apoptosis.

  3. 3.

    MicroRNAs are transcribed by RNA polymerase II and are later processed by endonuclease reactions into miRNAs.

  4. 4.

    Mural cells include vascular smooth muscle cells and pericytes which provide stability to blood vessels. These cells are aberrantly organized in tumor blood vessels and lead to leaky and a disorganized network of blood vessels.

  5. 5.

    The Yamanaka factors are four critical stem cell transcription factors whose collective expression induces reprogramming of differentiated cells and produced induced pluripotent stem cells. These four factors are Oct-4, Sox-2, c-Myc and Klf-4 (OKSM).

  6. 6.

    VEGF include five glycoproteins called VEGFA (most well characterized and referred to as VEGF), VEGFB, VEFC, VEGFD and placenta growth factor. VEGF binds to receptor tyrosine kinases VEGFR1, VEGFR2, VEGFR3 leading to downstream signaling that regulates angiogenesis.

Abbreviations

ABC:

ATP-binding cassette

AKT:

Protein kinase B

BCL-2:

B-cell lymphoma-2

BCR-ABL:

Breakpoint cluster region protein—Abelson murine leukemia viral oncogene homolog 1

Bv-8:

Bombina variegate peptide 8

CAF:

Cancer-associated fibroblasts

c-FLIP:

cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein

CpG:

Cytosine and guanine-rich sequences

CSC :

Cancer stem cell

DNMT:

DNA methyltransferase

ECM:

Extracellular matrix

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial-to-mesenchymal transition

ERK:

Extracellular signal-regulated kinase

FGF:

Fibroblast growth factor

HAT:

Histone acetyltransferase

HER:

Human epidermal growth factor receptor

HIF-1 α:

Hypoxia-inducible factor-1α

JAK:

Janus kinase

Klf-4:

Kruppel Like Factor 4

mAb:

Monoclonal antibody

MAPK:

Mitogen-activated protein kinase

MDR1:

Multidrug resistance protein 1

MEK:

Mitogen activated protein kinase kinase

MET:

Mesenchymal-to-epithelial transition

miRNA:

Micro-RNA

mTOR:

Mammalian target of rapamycin

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NP1:

Neuropilin

NSCLC:

Non-small cell lung cancer

OCT-1:

Organic-cation transporter-1

Oct-4:

Octamer-binding transcription factor 4

OP:

Oseltamivir phosphate

PARP:

Poly ADP-ribose polymerase

PDGF:

Platelet-derived growth factor

PI3K:

Phosphoinositide 3-kinase

PIGF:

Placental growth factor

RTKs:

Receptor tyrosine kinases

STAT3:

Signal transducer and activator of transcription 3

TAM:

Tumor-associated macrophage

TGF-α:

Transforming growth factor alpha

TKI:

Tyrosine kinase inhibitors

TME:

Tumor microenvironment

VEGF:

Vascular endothelial growth factor

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    Manpreet Sambi & Myron R. Szewczuk

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    Myron R. Szewczuk

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    Manpreet Sambi

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Sambi, M., Szewczuk, M.R. (2019). Introduction to the Acquisition of Resistance to Targeted Therapy. In: Szewczuk, M., Qorri, B., Sambi, M. (eds) Current Applications for Overcoming Resistance to Targeted Therapies. Resistance to Targeted Anti-Cancer Therapeutics, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-030-21477-7_1

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