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Cancer Stem Cells in Lung Cancer: Roots of Drug Resistance and Targets for Novel Therapeutic Strategies

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Cancer Stem Cell Resistance to Targeted Therapy

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 19))

Abstract

Lung cancer represents the leading cause of cancer-related deaths worldwide due to its high incidence and the lack of effective therapies. Current pharmacological strategies for the treatment of advanced stage disease are in fact largely ineffective mostly due to the emergence of drug resistance. The cancer stem cell (CSC) hypothesis suggests that treatment failure and tumor relapse may be explained by the existence of a subset of self-renewing cancer cells endowed with tumor-initiating potential which are able to escape conventional and targeted therapies and to regenerate tumors.

In this chapter we will first focus on the description of studies which led to identification and characterization of CSCs in lung cancer according to their expression of specific markers and/or functional properties and will discuss the potential clinical value of CSC-related markers to predict patients’ outcome and response to therapies. We will next review evidences supporting the proposed mechanisms of resistance of CSCs to chemotherapy and targeted therapies and in particular intrinsic CSCs’ properties such as enhanced activation of the DNA damage repair machinery and anti-apoptotic signaling, increased expression of drug transporters, activation of self-renewal pathways, and quiescence status. The ability of tumor microenvironment (TME)-derived signals to modulate CSC phenotype, especially through the induction of epithelial mesenchymal transition, has also been demonstrated to contribute to drug resistance. Here we will discuss the interconnection among TME signals, modulation/generation of CSC, and development of resistance to both conventional and targeted therapy in lung cancer. Finally we will present novel strategies based on targeting of specific pathways activated in CSCs or able to impair the cross talk between TME and CSCs and aimed at eradication of the CSC subsets, which have been already tested or are currently under investigation in clinical trials in advanced lung cancer.

Despite some still ongoing controversies regarding the best strategy/markers to define the stem cell population in lung cancer, several evidences support the resistance of lung CSC to conventional and targeted therapies providing a new perspective for the understanding of drug resistance mechanisms and indicating the path for development of innovative targeted therapies that may ultimately improve clinical outcome of lung cancer patients.

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Abbreviations

ABC:

ATP-binding cassette

ADC:

Adenocarcinoma

ALCAM:

Activated leukocyte cell adhesion molecule

ALDH:

Aldehyde dehydrogenase

AML:

Acute myeloid leukemia

ATRA:

All-trans retinoic acid

CAF:

Cancer-associated fibroblast

CSC:

Cancer stem cells

CXCR4:

Chemokine receptor type 4

DDR:

DNA damage response

DFS:

Disease-free survival

Dhh:

Desert hedgehog

DSBs:

Double-strand breaks

Dvl:

Disheveled proteins

EGFR:

Epidermal growth factor receptor

EGFR-TKI:

Epidermal growth factor receptor tyrosine kinase inhibitor

EMT:

Epithelial to mesenchymal transition

EPCAM :

Epithelial cell adhesion molecule

Hh:

Hedgehog

Ihh:

Indian hedgehog

IL-6:

Interleukin-6

LC:

Large cell carcinoma

MIC:

Metastasis initiating cell

MMP:

Metalloproteinase

NSCLC:

Non-small cell lung cancer

PDX:

Patient-derived xenograft

PTCH:

Patched

SCC:

Squamous-cell carcinoma

SDF1:

Stromal cell-derived factor 1

Shh:

Sonic hedgehog

SP:

Side population

TGF-β:

Transforming growth factor beta

TKIs:

Tyrosine kinase inhibitors

TME:

Tumor microenvironment

VEGFR:

Vascular endothelial growth factor receptor

ZEB:

Zinc finger E-box-binding

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Financial Support

This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC) Special Program 12,162 (ED12162 to LR and GS) and IG16847 (to LR).

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No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Cecilia Gardelli, Gabriella Sozzi, Luca Roz & Giulia Bertolini

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  1. Cecilia Gardelli
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  2. Gabriella Sozzi
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  3. Luca Roz
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  4. Giulia Bertolini
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Correspondence to Luca Roz or Giulia Bertolini .

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Editors and Affiliations

  1. Research Department, Sidra Medicine, Doha, Qatar

    Cristina Maccalli

  2. Department of DIBIMIS, University of Palermo, Laboratory of Cellular and Molecular Pathophysiology, Palermo, Italy

    Matilde Todaro

  3. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Soldano Ferrone

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Gardelli, C., Sozzi, G., Roz, L., Bertolini, G. (2019). Cancer Stem Cells in Lung Cancer: Roots of Drug Resistance and Targets for Novel Therapeutic Strategies. In: Maccalli, C., Todaro, M., Ferrone, S. (eds) Cancer Stem Cell Resistance to Targeted Therapy. Resistance to Targeted Anti-Cancer Therapeutics, vol 19. Springer, Cham. https://doi.org/10.1007/978-3-030-16624-3_3

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