Cutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways

doi:10.1016/j.jaad.2014.07.033

Journal of the American Academy of Dermatology

Volume 72, Issue 2, February 2015, Pages 221-236

https://doi.org/10.1016/j.jaad.2014.07.033 Get rights and content

The last decade has spawned an exciting new era of oncotherapy in dermatology, including the development of targeted therapies for metastatic melanoma and basal cell carcinoma. Along with skin cancer, deregulation of the PI3K-AKT-mTOR and RAS-RAF-MEK-ERK intracellular signaling pathways contributes to tumorigenesis of a multitude of other cancers, and inhibitors of these pathways are being actively studied. Similar to other classes of targeted therapies, cutaneous adverse effects are among the most frequent toxicities observed with mitogen-activated protein kinase pathway inhibitors, PI3K-AKT-mTOR inhibitors, hedgehog signaling pathway inhibitors, and immunotherapies. Given the rapid expansion of these families of targeted treatments, dermatologists will be essential in offering dermatologic supportive care measures to cancer patients being treated with these agents. Part II of this continuing medical education article reviews skin-related adverse sequelae, including the frequency of occurrence and the implications associated with on- and off-target cutaneous toxicities of inhibitors of the RAS-RAF-MEK-ERK pathway, PI3K-AKT-mTOR pathway, hedgehog signaling pathway, and immunotherapies.

Section snippets

RAS-RAF-MEK-ERK pathway

The RAS-RAF-MEK-ERK (mitogen-activated protein kinase [MAPK]) pathway is one of the most frequently deregulated signaling pathways leading to increased cellular proliferation in a broad spectrum of cancers. Patients who are taking inhibitors of the MAPK pathway frequently present with cutaneous adverse effects (AEs). The extensive interaction of the MAPK pathway with the PI3K-AKT-mammalian target of rapamycin (mTOR) pathway by sharing common inputs and activation through oncogenic RAS (Fig 1)

RAF inhibitors

Key points

•
Cutaneous eruptions, keratotic squamoproliferative lesions, and photosensitivity are among the most debilitating skin-related adverse effects of RAF inhibitors
•
Preventative measures and conservative treatments generally control most drug-related adverse effects; surgical treatment may be needed for select aggressive neoplasms
•
Close interval follow-up appointments optimize supportive care for RAF inhibitor patients, because skin toxicities are numerous

BRAF, an upstream activator in the MAPK

MEK inhibitors

Key points

•
The side effect profile of MEK inhibitors more closely mirrors that of epidermal growth factor receptor inhibitors rather than RAF
•
Combination use of MEK and RAF inhibitors improves efficacy and obviates many cutaneous toxicities

Upstream mutations at the level of a tyrosine kinase (ie, epidermal growth factor receptor [EGFR]), RAS, or BRAF can drive constitutive activation within the Raf/MEK/Erk pathway, converging on MEK proteins (MEK1 and MEK2), leading to malignant behavior of cells,

PI3K-AKT-mTOR pathway

Aberrant activation of the PI3K-AKT-mTOR pathway occurs in most human malignancies, either from PTEN inactivation or through oncogenic PI3K activity.⁷⁵ Mutated AKT may also independently activate the PI3K-AKT-mTOR signaling pathway in some tumor types.76, 77 Inhibitors of many targets within this pathway are actively being developed, but we will focus only on the cutaneous toxicities of mTOR inhibitors in this section. Data for PI3K inhibitors, AKT inhibitors, and dual inhibitors within the

mTOR inhibitors

Key points

•
Stomatitis is the most common adverse effect related to therapy with mTOR inhibitors and may necessitate dose adjustment in some cases
•
Inflammatory eruptions of different types occur with frequency, however these are rarely severe

The PI3K-AKT-mTOR signaling cascade is an upregulated pathway in multiple malignancies. Beginning with rapamycin, other mTOR inhibitors with enhanced pharmacokinetics and antiproliferative properties, including temsirolimus and everolimus, have now been approved by the

Hedgehog signaling pathway inhibitors

Key points

•
Alopecia is generally reversible and involves <50% of scalp hair; however, widespread hair loss may be seen
•
Taste disturbance occurs in ≤75% of patients; however, it prompts change in diet habits in a smaller subset of patients

Nearly all basal cell carcinomas have been shown to contain genetic alterations in the hedgehog signaling pathway (HhSP)—the most common being the aberrations leading to loss of function of patched homologue 1 (PTCH1). This allows for constitutive activation of the

Immunomodulatory agents

Key points

•
Immune-related adverse effects may include dermatitis, pruritus, and vitiligo
•
Symptoms are dose-related, rarely severe, and reversible

Improved understanding of regulatory processes that limit the immune response to cancer has led to emergence of potent immunomodulatory anticancer therapies. This is well illustrated with the development of therapeutic antibodies targeting inhibitory receptors expressed by T cells, such as cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1

CTLA-4 inhibitors

Ipilimumab is a recombinant, human monoclonal antibody that binds to CTLA-4. The US Food and Drug Administration approved ipilimumab in 2011 based on increased overall survival in comparison to standard chemotherapy.¹¹² In addition to its antitumor activity, ipilimumab's immune activating mechanism also causes a heightened immune response against native cellular functions, resulting in a spectrum of autoimmune AEs. Autoimmune dermopathies are the most frequently observed (in 40% of patients),

PD-1 inhibitors

The PD-1 inhibitors nivolumab (BMS-936558) and pembrolizumab (formerly lambrolizumab; MK-3475) provided progression-free survival in ≤41% and objective responses in ≤28% of patients in recent studies119, 120 and sustained tumor regression in those with disease progression while taking ipilimumab.120, 121 Additional trials are underway for melanoma, renal cell carcinoma, and non–small cell lung carcinoma. Autoimmune AEs similar to ipilimumab have been seen thus far in clinical trials.119, 122,

Conclusion

Cutaneous AEs are among the most frequently observed with many targeted therapies. Dermatologists can provide a useful role in minimizing the impact of skin-related toxicities, thereby influencing the need for dose-reduction or drug stoppage. With continued development of more targeted therapies, providers caring for those with cutaneous conditions will become integral components to the multidisciplinary approach of oncologic care.

We thank Lisa Litzenberger for her generous assistance in the

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: Funding sources: None.

: Conflicts of interest: None declared.

: Date of release: February 2015

: Expiration date: February 2018

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Continuing medical educationCutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways

Section snippets

RAS-RAF-MEK-ERK pathway

RAF inhibitors

MEK inhibitors

PI3K-AKT-mTOR pathway

mTOR inhibitors

Hedgehog signaling pathway inhibitors

Immunomodulatory agents

CTLA-4 inhibitors

PD-1 inhibitors

Conclusion

Hematol Oncol Clin North Am

Lancet

Cell

J Am Acad Dermatol

Ann Oncol

Lancet Oncol

Lancet

J Invest Dermatol

Dermatol Online J

Crit Rev Oncol Hematol

J Invest Dermatol

Eur J Cancer

Am J Transplant

Lancet

Clin Genitourin Cancer

Kidney Int

Semin Oncol

J Am Acad Dermatol

The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer

Clin Cancer Res

Distinct sets of genetic alterations in melanoma

N Engl J Med

Patterns of somatic mutation in human cancer genomes

Nature

Mutations of the BRAF gene in human cancer

Nature

BRAF mutations in hairy-cell leukemia

N Engl J Med

Improved survival with vemurafenib in melanoma with BRAF V600E mutation

N Engl J Med

Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations

N Engl J Med

Inhibition of mutated, activated BRAF in metastatic melanoma

N Engl J Med

Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib

N Engl J Med

Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities

Br J Dermatol

Acute kidney injury in patients with severe rash on vemurafenib treatment for metastatic melanomas

Br J Dermatol

Vemurafenib sensitivity skin reaction after ipilimumab

N Engl J Med

RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth

Nature

RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)

Nature

RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF

Nature

BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling

Sci Signal

RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors

N Engl J Med

RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors

J Clin Oncol

Progression of RAS-mutant leukemia during RAF inhibitor treatment

N Engl J Med

Merkel cell polyomavirus and HPV-17 associated with cutaneous squamous cell carcinoma arising in a patient with melanoma treated with the BRAF inhibitor dabrafenib

JAMA Dermatol

Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma

Br J Dermatol

Induction of cutaneous squamous cell carcinomas by RAF inhibitors: cause for concern?

J Clin Oncol

Squamoproliferative lesions arising in the setting of BRAF inhibition

Am J Dermatopathol

Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development

Br J Dermatol

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Br J Dermatol

Continuing medical education
Cutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways