Inhibiting EGFR Signaling Holds Promise for Treating Palmoplantar Keratodermas.

View Large Image Figure ViewerDownload Hi-res image Download (PPT) PC is a rare condition (∼10 thousand cases worldwide) featuring anomalies that affect ectoderm-derived appendages, including nail dystrophy, sebaceous cysts, natal teeth, oral leukokeratosis, and PPK (Leachman et al., 2005Leachman S.A. Kaspar R.L. Fleckman P. Florell S.R. Smith F.J. McLean W.H. et al.Clinical and pathological features of pachyonychia congenita.J Investig Dermatol Symp Proc. 2005; 10: 3-17Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). PPK consists of extreme thickening of the skin of palms and especially soles and develops primarily in areas of skin experiencing high pressure or compression stress. Histologically, there is a dramatic thickening of the living and stratum corneum compartments, known as acanthosis and hyperkeratosis, respectively, in the palmar and especially the plantar epidermis in PC (Cao et al., 2015Cao Y.A. Hickerson R.P. Seegmiller B.L. Grapov D. Gross M.M. Bessette M.R. et al.Gene expression profiling in pachyonychia congenita skin.J Dermatol Sci. 2015; 77: 156-165Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Very severe pain emanate from PC-associated PPK, on a daily basis, making routine tasks and activities very challenging. PC does not impact lifespan but dramatically impacts QOL (Leachman et al., 2005Leachman S.A. Kaspar R.L. Fleckman P. Florell S.R. Smith F.J. McLean W.H. et al.Clinical and pathological features of pachyonychia congenita.J Investig Dermatol Symp Proc. 2005; 10: 3-17Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). The basis for the chronic and intense pain that occurs in PC-associated PPK or other forms of painful PPK is largely unknown (Weinberg et al., 2020Weinberg R.L. Coulombe P.A. Polydefkis M. Caterina M.J. Pain mechanisms in hereditary palmoplantar keratodermas.Br J Dermatol. 2020; 182: 543-551Crossref PubMed Scopus (7) Google Scholar). As detailed below, there is as of yet no effective treatment for PC aside from palliative measures that provide short-term and partial relief (Leachman et al., 2005Leachman S.A. Kaspar R.L. Fleckman P. Florell S.R. Smith F.J. McLean W.H. et al.Clinical and pathological features of pachyonychia congenita.J Investig Dermatol Symp Proc. 2005; 10: 3-17Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). Individuals suffering from PC benefit from transformative support provided by the Pachyonychia Congenita Project, a highly effective patient advocacy organization founded nearly 20 years ago by Mary Schwartz, a mother in-law and grandmother to PC sufferers (see www.pachyonychia.org).Clinical Implications•Pachyonychia congenita (PC) is a rare disorder caused by mutations in specific keratin genes and featuring painful palmoplantar keratoderma (PPK).•A new study reports on a hyperactive EGFR signaling signature in PC-associated PPK and on the effectiveness of the EGFR inhibitor erlotinib in attenuating PPK in three individuals with PC.•Hyperactive EGFR signaling is emerging as a shared molecular phenotype in a subset of PPK disorders and may contribute to pain in PC-associated PPK.•In their recent article in the Journal of Investigative Dermatology, a team led by Alain Hovnanian (Paris, France) reports on promising findings when using erlotinib, an inhibitor of the EGFR, to treat the debilitating and painful palmoplantar keratoderma (PPK) that occurs in individuals with pachyonychia congenita (PC) (Basset et al., 2022Basset J. Marchal L. Hovnanian A. EGFR signaling is overactive in pachyonychia congenita: effective treatment with oral erlotinib.J Invest Dermatol. 2022; 143: 294-304.e8Google Scholar). •Pachyonychia congenita (PC) is a rare disorder caused by mutations in specific keratin genes and featuring painful palmoplantar keratoderma (PPK).•A new study reports on a hyperactive EGFR signaling signature in PC-associated PPK and on the effectiveness of the EGFR inhibitor erlotinib in attenuating PPK in three individuals with PC.•Hyperactive EGFR signaling is emerging as a shared molecular phenotype in a subset of PPK disorders and may contribute to pain in PC-associated PPK.•In their recent article in the Journal of Investigative Dermatology, a team led by Alain Hovnanian (Paris, France) reports on promising findings when using erlotinib, an inhibitor of the EGFR, to treat the debilitating and painful palmoplantar keratoderma (PPK) that occurs in individuals with pachyonychia congenita (PC) (Basset et al., 2022Basset J. Marchal L. Hovnanian A. EGFR signaling is overactive in pachyonychia congenita: effective treatment with oral erlotinib.J Invest Dermatol. 2022; 143: 294-304.e8Google Scholar). PC is caused by dominantly acting small mutations that affect the coding sequence of any one of five specific keratin genes, keratin (K6RTA, KRT6B, KRT6C, KRT16, or KRT17 (Leachman et al., 2005Leachman S.A. Kaspar R.L. Fleckman P. Florell S.R. Smith F.J. McLean W.H. et al.Clinical and pathological features of pachyonychia congenita.J Investig Dermatol Symp Proc. 2005; 10: 3-17Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar; McLean et al., 1995McLean W.H. Rugg E.L. Lunny D.P. Morley S.M. Lane E.B. Swensson O. et al.Keratin 16 and keratin 17 mutations cause pachyonychia congenita.Nat Genet. 1995; 9: 273-278Crossref PubMed Scopus (289) Google Scholar). The protein products of keratin genes form cytoskeletal intermediate filaments, and the polymerization process requires the participation of types I and II keratin proteins in a 1:1 molar ratio. In mature skin, coexpression of type II KRT6A, KRT6B, and KRT6C paralogs and type I KRT16 and KRT17 occurs in specific subcompartments of all ectoderm epithelial appendages (nail, glands, hair, oral mucosa, etc.) and in the thicker epidermis of palm and sole skin. This expression pattern accounts for the tissues primarily affected in PC (McLean et al., 1995McLean W.H. Rugg E.L. Lunny D.P. Morley S.M. Lane E.B. Swensson O. et al.Keratin 16 and keratin 17 mutations cause pachyonychia congenita.Nat Genet. 1995; 9: 273-278Crossref PubMed Scopus (289) Google Scholar). In addition, the KRT6A, KRT6B, KRT16, and KRT17 genes are robustly inducible after stress, which results in higher expression levels of the proteins they code for and likely contributes to the exaggerated character of PC symptoms, including PPK (Cao et al., 2015Cao Y.A. Hickerson R.P. Seegmiller B.L. Grapov D. Gross M.M. Bessette M.R. et al.Gene expression profiling in pachyonychia congenita skin.J Dermatol Sci. 2015; 77: 156-165Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar; Lessard et al., 2013Lessard J.C. Piña-Paz S. Rotty J.D. Hickerson R.P. Kaspar R.L. Balmain A. et al.Keratin 16 regulates innate immunity in response to epidermal barrier breach.Proc Natl Acad Sci USA. 2013; 110: 19537-19542Crossref PubMed Scopus (119) Google Scholar; Zieman and Coulombe, 2020Zieman A.G. Coulombe P.A. Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment.Br J Dermatol. 2020; 182: 564-573Crossref PubMed Scopus (21) Google Scholar). The majority of PC-causing mutations are missense alleles that map to various subdomains in K6A, K6B, K6C, K16, and K17 proteins (Leachman et al., 2005Leachman S.A. Kaspar R.L. Fleckman P. Florell S.R. Smith F.J. McLean W.H. et al.Clinical and pathological features of pachyonychia congenita.J Investig Dermatol Symp Proc. 2005; 10: 3-17Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). Historically, two main types of PC—type 1 or Jadahsson‒Lewandowsky and type 2 or Jackson‒Lawler—were recognized on the basis of partially distinct, recurring clinical features (McLean et al., 1995McLean W.H. Rugg E.L. Lunny D.P. Morley S.M. Lane E.B. Swensson O. et al.Keratin 16 and keratin 17 mutations cause pachyonychia congenita.Nat Genet. 1995; 9: 273-278Crossref PubMed Scopus (289) Google Scholar). Mutations in KRT6A or KRT16 usually cause type I PC, whereas mutations in KRT17 are preferentially associated with type II PC (Leachman et al., 2005Leachman S.A. Kaspar R.L. Fleckman P. Florell S.R. Smith F.J. McLean W.H. et al.Clinical and pathological features of pachyonychia congenita.J Investig Dermatol Symp Proc. 2005; 10: 3-17Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). The rationale for this phenotype‒genotype correlation is not well-understood, and possibly relevant to this, the penetrance of various PC traits is subject to modifier effects in humans and in relevant mouse models. Given this heterogeneity along with the breadth of PPK etiologies, a formal PC diagnosis usually requires DNA sequencing. PPK occurs in several skin disorders and can be caused by mutations in a large and diverse array of genes that code for, other than keratin, adhesion proteins (DSP, PKP1, DSG1, JUP), ion channels (TRPV3, AQP5, GJB2, GJA1), protease regulators and differentiation effectors (SERPINB7, loricrin gene LOR, WNT10A), etc. (Zieman and Coulombe, 2020Zieman A.G. Coulombe P.A. Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment.Br J Dermatol. 2020; 182: 564-573Crossref PubMed Scopus (21) Google Scholar). It appears likely that many of these proteins are integrated into a functional network tasked with regulating differentiation and homeostasis in the thick epidermis of palmoplantar skin, in ways that remain to be deciphered. Progress made in the study or treatment of any form of PPK is poised to significantly advance our understanding of the inner workings of the complex palmoplantar skin ecosystem and the dire consequences of its dysregulation. For instance, studies of Krt16-null mice, which develop PPK-like lesions that resemble PC/PPK in footpad skin, highlighted the successive involvement of defects in keratinocyte differentiation, reduction‒oxidation imbalance and oxidative stress (secondary to impaired NRF2 signaling), and misregulated innate immunity, underscoring the complexity of this condition (see Zieman and Coulombe, 2020Zieman A.G. Coulombe P.A. Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment.Br J Dermatol. 2020; 182: 564-573Crossref PubMed Scopus (21) Google Scholar for a review). In the study that prompted this commentary, Basset et al., 2022Basset J. Marchal L. Hovnanian A. EGFR signaling is overactive in pachyonychia congenita: effective treatment with oral erlotinib.J Invest Dermatol. 2022; 143: 294-304.e8Google Scholar postulated that EGFR-dependent signaling is hyperactive in PPK lesions of individuals with PPK and that Erlotinib—a reversible inhibitor that targets the kinase activity of the human type 1 EGFR—could be effective in treating PC-associated PPK. A body of literature substantiates the validity of the astute claims made by the authors. First, several attributes of PC-associated PPK, including enhanced keratinocyte proliferation, aberrant keratinocyte differentiation, acanthosis, hyperkeratosis, dysregulated innate immunity, and de novo angiogenesis, are promoted by hyperactive EGFR signaling in skin tissue (Wang et al., 2019Wang S. Zhang Z. Peng H. Zeng K. Recent advances on the roles of epidermal growth factor receptor in psoriasis.Am J Transl Res. 2019; 11: 520-528PubMed Google Scholar). Second, previous studies (Greco et al., 2020Greco C. Leclerc-Mercier S. Chaumon S. Doz F. Hadj-Rabia S. Molina T. et al.Use of epidermal growth factor receptor inhibitor erlotinib to treat palmoplantar keratoderma in patients with Olmsted syndrome caused by TRPV3 mutations.JAMA Dermatol. 2020; 156: 191-195Crossref PubMed Scopus (29) Google Scholar; Kenner-Bell et al., 2010Kenner-Bell B.M. Paller A.S. Lacouture M.E. Epidermal growth factor receptor inhibition with erlotinib for palmoplantar keratoderma.J Am Acad Dermatol. 2010; 63: e58-e59Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar), including one led by Hovnanian (Zhang et al., 2020Zhang A. Duchatelet S. Lakdawala N. Tower R.L. Diamond C. Marathe K. et al.Targeted inhibition of the epidermal growth factor receptor and mammalian target of rapamycin signaling pathways in Olmsted syndrome.JAMA Dermatol. 2020; 156: 196-200Crossref PubMed Scopus (14) Google Scholar), showed that hyperactive EGFR signaling occurs in the setting of the PPK associated with Olmsted syndrome (OS), a congenital disorder caused by mutations in TRPV3. The TRPV3 protein encodes a temperature-sensitive calcium channel that interacts with and modulates the activity of EGFR in skin keratinocytes (Cheng et al., 2010Cheng X. Jin J. Hu L. Shen D. Dong X.P. Samie M.A. et al.TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation.Cell. 2010; 141: 331-343Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). Orally administered erlotinib was effective in treating PPK and was well-tolerated in small cohorts of individuals with OS (Greco et al., 2020Greco C. Leclerc-Mercier S. Chaumon S. Doz F. Hadj-Rabia S. Molina T. et al.Use of epidermal growth factor receptor inhibitor erlotinib to treat palmoplantar keratoderma in patients with Olmsted syndrome caused by TRPV3 mutations.JAMA Dermatol. 2020; 156: 191-195Crossref PubMed Scopus (29) Google Scholar; Kenner-Bell et al., 2010Kenner-Bell B.M. Paller A.S. Lacouture M.E. Epidermal growth factor receptor inhibition with erlotinib for palmoplantar keratoderma.J Am Acad Dermatol. 2010; 63: e58-e59Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar; Zhang et al., 2020Zhang A. Duchatelet S. Lakdawala N. Tower R.L. Diamond C. Marathe K. et al.Targeted inhibition of the epidermal growth factor receptor and mammalian target of rapamycin signaling pathways in Olmsted syndrome.JAMA Dermatol. 2020; 156: 196-200Crossref PubMed Scopus (14) Google Scholar). Third, missense mutations in RHBDF2 result in PPK and increased susceptibility to esophageal cancer. The RHBDF2 gene codes for iRHOM2, a catalytically inactive member of the rhomboid family of intramembrane serine proteases that enhance the ADAM17-dependent shedding of several EGFR ligands (Brooke et al., 2014Brooke M.A. Etheridge S.L. Kaplan N. Simpson C. O'Toole E.A. Ishida-Yamamoto A. et al.iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function.Hum Mol Genet. 2014; 23: 4064-4076Crossref PubMed Scopus (60) Google Scholar). Finally, the proximal promoters of the KRT6 and KRT16 genes contain EGF-response elements (Jiang et al., 1993Jiang C.K. Magnaldo T. Ohtsuki M. Freedberg I.M. Bernerd F. Blumenberg M. Epidermal growth factor and transforming growth factor alpha specifically induce the activation- and hyperproliferation-associated keratins 6 and 16.Proc Natl Acad Sci USA. 1993; 90: 6786-6790Crossref PubMed Scopus (170) Google Scholar), and the ectopic overexpression of human K16 protein elicits a hyperactive EGFR signaling phenotype in transgenic mouse skin (Paladini and Coulombe, 1998Paladini R.D. Coulombe P.A. Directed expression of keratin 16 to the progenitor basal cells of transgenic mouse skin delays skin maturation.J Cell Biol. 1998; 142: 1035-1051Crossref PubMed Scopus (69) Google Scholar), suggesting that some of the PC keratins and EGFR may be part of a positive feedback loop mechanism in skin keratinocytes. Basset et al., 2022Basset J. Marchal L. Hovnanian A. EGFR signaling is overactive in pachyonychia congenita: effective treatment with oral erlotinib.J Invest Dermatol. 2022; 143: 294-304.e8Google Scholar obtained biopsies of PPK lesions from four genetically confirmed cases of PC and, owing to restrictions in sample size and availability, performed microscopy-based analyses on skin tissue sections with a focus on readouts relevant to EGFR activity status. Using in situ hybridization, the authors discovered that the signal for mRNAs coding for several EGFR ligands, epiregulin (EREG), TGFα (TGFα), amphiregulin (AREG), and HB-EGF are significantly increased, as are the signals for VEGF-A and TRPV3, with the latter providing an intriguing potential connection to OS-related PPK. The authors found enhanced immunostaining for the EGFR (also known as HER1) and HER2 receptor antigens; for the phosphorylated forms of the ribosomal protein S6 antigen, an indicator of activity level for the EGFR-responsive mTOR kinase; and for extracellular signal‒regulated kinases 1/2. Together, these findings are consistent with increased EGFR-dependent signaling in active PPK lesions relative to clinically uninvolved (control) skin. Building on these observations and their previous experience with OS, Basset et al., 2022Basset J. Marchal L. Hovnanian A. EGFR signaling is overactive in pachyonychia congenita: effective treatment with oral erlotinib.J Invest Dermatol. 2022; 143: 294-304.e8Google Scholar treated three patients with PC with oral erlotinib for 6‒8 months. The treatment was well-tolerated (despite acneiform lesions in two patients) and led to an early, drastic, and sustained reduction of the PPK and neuropathic pain with a major improvement in QOL indices. Whereas a role for hyperactive EGFR signaling in eliciting PPK lesions may have been expected given clues from the literature, the potential connection between this pathway and pain is novel in the setting of PC (Weinberg et al., 2020Weinberg R.L. Coulombe P.A. Polydefkis M. Caterina M.J. Pain mechanisms in hereditary palmoplantar keratodermas.Br J Dermatol. 2020; 182: 543-551Crossref PubMed Scopus (7) Google Scholar). The findings by Basset et al., 2022Basset J. Marchal L. Hovnanian A. EGFR signaling is overactive in pachyonychia congenita: effective treatment with oral erlotinib.J Invest Dermatol. 2022; 143: 294-304.e8Google Scholar prompted us to reinterrogate a previously reported genome-wide survey of gene expression in the PPK-like lesions arising in the footpad skin of Krt16-null mice (Zieman et al., 2019Zieman A.G. Poll B.G. Ma J. Coulombe P.A. Altered keratinocyte differentiation is an early driver of keratin mutation-based palmoplantar keratoderma.Hum Mol Genet. 2019; 28: 2255-2270Crossref PubMed Scopus (14) Google Scholar). This investigation revealed that the mRNA transcript levels for multiple EGFR ligands, including epigenin (Epgn) (up to 12.1-fold; P < 0.00008), HB-EGF (Hbegf) (up to 4.3-fold; P < 0.00017), amphiregulin (Areg) (up to 4.0-fold; P < 0.0048), and TGFα (Tgfα) (up to 1.4-fold; P < 0.013), as well as several EGFR-responsive genes, including Krt6b (up to 13.9-fold; P < 0.00047), Krt6a (up to 4.3-fold; P < 0.00022), S100a7a (up to 5.6-fold; P < 0.00045), and Vegfa (up to 1.6-fold; P < 0.0017), are each significantly elevated, whereas those coding for relevant receptors, for example, Egfr and Erb2, occur at normal levels. Such findings support the notion that hyperactive EGFR signaling may play a key role in the genesis of focal PPK lesions, further validate the relevance of the Krt16-null mice as a model for PC-associated PPK, and highlight the importance of assessing EGFR signaling and the efficacy of oral erlotinib on a larger scale in PC. Efforts made to date toward exploring the effectiveness of various drugs and approaches to treat PC-associated PPK have been vigorous but have yielded modest success owing to a combination of factors. Such approaches have included the use of keratin-mutant allele-specific small interfering RNAs, drugs that target mTOR signaling (rapamycin), cholinergic signaling (Botox) or retinoic acid signaling, and statins (see Zieman and Coulombe, 2020Zieman A.G. Coulombe P.A. Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment.Br J Dermatol. 2020; 182: 564-573Crossref PubMed Scopus (21) Google Scholar for a recent review). The study by Basset et al., 2022Basset J. Marchal L. Hovnanian A. EGFR signaling is overactive in pachyonychia congenita: effective treatment with oral erlotinib.J Invest Dermatol. 2022; 143: 294-304.e8Google Scholar using erlotinib thus provides a most welcome and exciting advance in this field. Intriguingly, as mentioned earlier, these findings build on a comparable outcome when using oral erlotinib in individuals with OS (Greco et al., 2020Greco C. Leclerc-Mercier S. Chaumon S. Doz F. Hadj-Rabia S. Molina T. et al.Use of epidermal growth factor receptor inhibitor erlotinib to treat palmoplantar keratoderma in patients with Olmsted syndrome caused by TRPV3 mutations.JAMA Dermatol. 2020; 156: 191-195Crossref PubMed Scopus (29) Google Scholar; Kenner-Bell et al., 2010Kenner-Bell B.M. Paller A.S. Lacouture M.E. Epidermal growth factor receptor inhibition with erlotinib for palmoplantar keratoderma.J Am Acad Dermatol. 2010; 63: e58-e59Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar; Zhang et al., 2020Zhang A. Duchatelet S. Lakdawala N. Tower R.L. Diamond C. Marathe K. et al.Targeted inhibition of the epidermal growth factor receptor and mammalian target of rapamycin signaling pathways in Olmsted syndrome.JAMA Dermatol. 2020; 156: 196-200Crossref PubMed Scopus (14) Google Scholar), thereby highlighting the possibility that enhanced EGFR signaling may be a molecular trait that is shared across PPK disorders of distinct etiologies. Yet, many issues need to be addressed going forward. EGFR is a prominent receptor tyrosine kinase (RTK) capable of activating multiple cellular pathways, including the Ras/Raf/MAPK, phosphoinositide-3 kinase/PTEN/protein kinase B, and Jak/signal transducer and activator of transcription kinase cascades, which respectively exert a significant impact on cell proliferation, metabolism, and differentiation (Wee and Wang, 2017Wee P. Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways.Cancers (Basel). 2017; 9: 52Crossref PubMed Scopus (870) Google Scholar). Given that EGFR is highly expressed in skin and also gastrointestinal epithelial cells, it comes as no surprise that the most prominent side effects of oral erlotinib are cutaneous lesions and rashes and diarrhea. As part of the next steps, the role of EGFR signaling in the genesis, character, and/or maintenance of PPK; its role in giving rise to significant pain; and the systemic and long-term effects of inhibiting an RTK using orally administered drugs should be carefully assessed as erlotinib (and related drugs) is tested on a larger scale in individuals with PC. Pierre A. Coulombe: http://orcid.org/0000-0003-0680-2373 Amanda Orosco: http://orcid.org/0000- 0003-0930-6746 The authors state no conflict of interest. The authors are grateful to members of the Coulombe laboratory for support and to Carole Parent for editorial advice. AO received support from the National Institutes of Health T32 grant GM145470 awarded to the training program in Cellular and Molecular Biology at the University of Michigan Medical School. EGFR Signaling Is Overactive in Pachyonychia Congenita: Effective Treatment with Oral ErlotinibJournal of Investigative DermatologyVol. 143Issue 2PreviewPachyonychia congenita (PC) is a rare keratinizing disorder characterized by painful palmoplantar keratoderma for which there is no standard current treatment. PC is caused by dominant mutations in keratin (K) K6A, K6B, K6C, K16, or K17 genes involved in stress, wound healing, and epidermal barrier formation. Mechanisms leading to pain and painful palmoplantar keratoderma in PC remain elusive. In this study, we show overexpression of EGFR ligands epiregulin and TGF-α as well as HER1‒EGFR and HER2 in the upper spinous layers of PC lesions. Full-Text PDF Open Access