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Current Applications for Overcoming Resistance to Targeted Therapies pp 223–258Cite as

Emerging Novel Therapies in Overcoming Resistance to Targeted Therapy

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

Abstract

The recent development of small molecule inhibitors and monoclonal antibodies that target cancer-specific oncogenic driver mutations has significantly improved the outcomes of patients with various tumour types including chronic myeloid leukemia, non-small cell lung cancer and melanoma. Despite high rates of response, most patients will relapse within the first year of targeted therapy due to drug resistance. Although multiple mechanisms of resistance have been defined, these often lead to the re-activation of oncogene-regulated signaling or the activation of compensatory survival cascades. This chapter focusses on emerging therapeutic strategies to overcome and circumvent resistance to targeted therapies, with an emphasis on metastatic melanoma. A variety of therapeutic salvage approaches are being explored, including novel targeted agents, new combination therapies and consideration of drug timing and sequencing. Improved clinical trial design, treatment of earlier stage cancer patients and sensitive real-time monitoring of patient responses and resistance are critical for improving the durability of cancer targeted therapies.

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Notes

  1. 1.

    Response evaluation criteria in solid tumors (RECIST) is a set of guidelines used in the assessment of the change in tumor burden. It recommends evaluation of a maximum of five lesions (maximum two per organ) as target lesions. In addition, a pathological lymph node requires a short axis diameter of ≥15 mm to be assessable as target lesion. A complete response (CR) is disappearance of all target lesions or reduction of lymph node short axis to <10 mm, partial response (PR) is at least 30% decrease in the sum of diameters of target lesions and progressive disease (PD) is at least a 20% increase in the sum of diameters of target lesions or the appearance of new lesions and an absolute increase of at least 5 mm. Stable disease is defined as neither PR or PD.

Abbreviations

ALK:

Anaplastic lymphoma kinase

CI:

Confidence interval

CML:

Chronic myeloid leukemia

CTLA4:

Cytotoxic T-lymphocyte-associated protein 4

EGFR:

Epidermal growth factor receptor

FDA:

Food and drug administration

GIST:

Gastrointestinal stromal tumors

HR:

Hazard ratio

IGF1R:

Insulin-like growth factor 1 receptor

MAPK:

Mitogen-activated protein kinase

MITF:

Microphthalmia-associated transcription factor

mTOR:

Mammalian target of rapamycin

NF1:

Neurofibromin 1

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PD-1:

Programmed cell death protein 1

PDGFR:

Platelet-derived growth factor receptor

PFS:

Progression-free survival

PI3K:

Phosphoinositide 3-kinase

PTEN:

Phosphatase and tensin homologue

RECIST:

Response evaluation criteria in solid tumors

RTK:

Receptor tyrosine kinase

TK:

Tyrosine kinase

TKR:

Tyrosine kinase receptor

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Conflict of Interest

No potential conflicts of interest to disclose.

Funding: This work was supported by funding from NHMRC project grants 1130423 and 1093017. HR is supported by an NHMRC Research Fellowship.

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Authors and Affiliations

  1. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia

    Andreia V. Pinho, Jenny H. Lee & Helen Rizos

  2. Melanoma Institute Australia, Sydney, NSW, Australia

    Andreia V. Pinho, Jenny H. Lee & Helen Rizos

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  2. Jenny H. Lee
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Correspondence to Helen Rizos .

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  1. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Myron R. Szewczuk

  2. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Bessi Qorri

  3. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Manpreet Sambi

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Pinho, A.V., Lee, J.H., Rizos, H. (2019). Emerging Novel Therapies in Overcoming 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_8

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