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. 2026 Jun 4;53(11):1042–1050. doi: 10.1111/cup.70159

Dermatologic Toxicities Associated With Novel Pan‐RAS/RAF Inhibitors

Lin J He 1, Shaymaa Hegazy 1, Phyu P Aung 1, Priyadharsini Nagarajan 1, Fiorinda Muhaj 2, Adrienne N Choksi 2, Ana M Ciurea 2, Kelly C Nelson 2, Doina Ivan 1, Carlos A Torres‐ Cabala 1,2, Victor G Prieto 1,2, Jonathan L Curry 1,3,✉
PMCID: PMC13628425  PMID: 42244177

ABSTRACT

Background

The mitogen‐activated protein kinase (MAPK) pathway plays a key role in cell‐cycle regulation and tumor progression in cancer. Dermatologic toxicities (DTs) to newer pan‐RAS (RMC‐6236) and pan‐RAF (LXH254/naporafenib) inhibitors are emerging. Therefore, knowledge of the morphologic patterns of DTs from pan‐RAS/RAF inhibitors will enable quick diagnosis and appropriate management.

Methods

The clinical and histologic features of patients treated with pan‐RAS or pan‐RAF inhibitors for advanced stage RAS mutated malignancies were retrospectively reviewed.

Results

Associated DTs were identified in eight patients treated with either pan‐RAS (n = 4) or pan‐RAF (n = 4) plus MEK/ERK inhibitors for RAS mutated tumors (colorectal, lung, pancreatic, thyroid, melanoma). The patients ranged from 37 to 72 years of age. Five patients had initial clinical presentation of an acneiform eruption complicated by ulceration, flaccid vesicles, or diffuse exfoliative erythroderma. Maculopapular eruption, purpuric patches and papules, and eruptive dark nevi were the other clinical presentations. Skin biopsies were primarily inflammatory with histopathologic features of suppurative folliculitis (n = 2), dermal hypersensitivity reaction (n = 2), subcorneal acantholytic dermatosis (n = 1), subcorneal pustules (n = 1), ulcer (n = 1), and eruptive nevi (n = 1).

Conclusions

Treatment with novel pan‐RAS/RAF inhibitors exhibits a spectrum of DTs that exhibit some overlap with small molecule inhibitors that target the MAPK pathway.

Keywords: dermatologic toxicities, LTT462, LXH254, naporafenib, pan‐RAF, pan‐RAS, RMC6236, small molecule inhibitors

1. Introduction

The discovery of RAS and RAF driver mutations in human cancer, combined with the development of novel small molecule inhibitors (Nibs) targeting signal transduction pathways, have ushered in the era of mutation‐specific personalized cancer therapy. The mitogen‐activated protein kinase (MAPK) pathway is critical to the growth‐promoting signaling in RAS‐ and RAF‐mutated cancers [1]. The therapeutic efficacy of mutation‐selective and state‐selective RAS (inactive) Nibs designed to target mutant RAS protein (e.g., KRAS‐G12C) has been limited due to the emergence of resistance and the cyclical nature of and conformational changes in mutated RAS GTPase protein from RAS‐GDP‐bound (inactive state) to RAS‐GTP‐bound (active state) [2, 3, 4]. To circumvent these limitations, researchers engineered novel pan‐RAS inhibitors (e.g., RMC‐6236) to target wild‐type and mutant variants of RAS protein in its active (GTP‐bound) state [5].

An alternative strategy to block mutant RAS signaling is treatment with pan‐RAF inhibitors (e.g., naporafenib/LXH254) targeting wild‐type and mutant forms of BRAF and CRAF proteins at their ATP‐binding sites [6, 7, 8]. Pan‐RAF inhibitors have been indicated for treatment of tumors not responsive to BRAF Nibs as well as tumors with RAS mutations.

Dermatologic toxicities (DTs) associated with novel pan‐RAS and pan‐RAF inhibitors are starting to emerge and expand the spectrum of known Nib‐based DTs [9]. Recognition of the diverse histopathologic features of DTs in the era of targeted, personalized cancer therapy will be critical for clinical management of patients with adverse skin reactions. This case series will provide a detailed clinical and histopathologic feature of DTs in eight cancer patients treated with either pan‐RAS or pan‐RAF inhibitors.

2. Materials and Methods

This retrospective study was approved by the Institutional Review Board (IRB). When feasible, informed consent was obtained. A search of our institutional anatomical pathology database identified eight patients who experienced DTs associated with treatment of cancer with pan‐RAS/RAF inhibitors from 2022 to 2024. Each patient's clinical history, oncologic disease course, and treatment were retrieved, and the histopathologic features of their DTs were examined.

3. Results

The patients' ages ranged from 37 to 72 years (mean, 56 years). Six patients were male and two were female. The oncologic history of the patients included pancreatic ductal adenocarcinoma (n = 2), nonsmall cell lung carcinoma (n = 2), melanoma (n = 2), follicular thyroid cancer (n = 1), and colorectal cancer (n = 1). Four patients given the pan‐RAS inhibitor RMC6236 had tumors with KRAS codon 12/13 hotspot mutations (G12D/R/S and G13R). Also noted was a HRAS A155S mutation in one of these four patients. The remaining four patients received the pan‐RAF inhibitor naporafenib (LXH254) in combination with either the MEK inhibitor trametinib or ERK inhibitor LTT462. Tumors from these patients harbored either a KRAS non‐codon 12/13 hotspot mutation (Q61H) or NRAS Q61R/K mutation. The clinicopathologic features of the patients are summarized in Table 1.

TABLE 1.

Clinicopathologic features of eight patients presenting with dermatologic toxicities (DTs) associated with pan‐RAS/RAF inhibitors.

Patient Age (years) Sex Indications for targeted therapy Mutation Drug Tumor response to pan‐RAS/RAF inhibitors

Onset of DT

(Wks)

 Onset of DT to biopsy (Wks) Clinical presentation (location) Pathological findings Treatment of DT DT post‐treatment
#1 50 Male Metastatic nonsmall cell lung carcinoma KRAS G12S pan‐RAS inhibitor (RMC6236) AWD after 20 months and new brain metastasis 1 1.5 Diffuse acneiform eruption with multiple papules and pustules (scalp) Suppurative folliculitis Topical desonide, triamcinolone and clobetasol Significantly improved
#2 72 Male Metastatic pancreatic adenocarcinoma KRAS G12R pan‐RAS inhibitor (RMC6236) DOD after 8 months 1 1.5 Papular eruption (face and upper trunk) complicated by purpuric patches and papules (thighs) Superficial perivascular dermatitis with occasional eosinophils (DHR) and focal dermal purpura Topical desonide, triamcinolone and clobetasol Significantly improved
#3 58 Male Metastatic pancreatic adenocarcinoma KRAS G12D HRAS A155S pan‐RAS inhibitor (RMC6236) DOD after 6 months 2 16 Acneiform eruption with multiple papules and pustules complicated by eczematous patches/plaques with ulceration (forearm) Scale crust, ulceration and a minimal interstitial inflammatory infiltrate Topical clindamycin and desonide; po cephalaxin, topical clobetasol; topical mupirocin Significantly improved and ulceration resolved
#4 37 Female Metastatic poorly‐differentiated nonsmall cell lung carcinoma KRAS G13R pan‐RAS inhibitor (RMC6236) AWD after 6 months with partial response according to imaging 1 6 Acneiform eruption with multiple papules and pustules (scalp) complicated by crusted erosion, flaccid vesicles and papules (hands and shins) Spongiosis, subcorneal blister, focal acantholysis and neutrophils with features of pemphigus foliaceus Topical mupirocin and clobetasol; po acitretin Minimal improvement; subsequent flare; improved when pan‐RAS inhibitor was on hold
#5 63 Male Metastatic follicular thyroid cancer NRAS Q61K pan‐RAF inhibitor (LXH254) + Trametinib AWD after 15 months 8 9 Acneiform eruption with multiple papules and pustules (back, chest, face, and scalp) Suppurative folliculitis with rupture Topical clindamycin; PO linezolid; PO acitretin and topical triamcinolone and clobetasol Significantly improved and well‐controlled
#6 46 Female Metastatic colorectal cancer KRAS Q61H pan‐RAF inhibitor (LXH254) + Trametinib AWD after 12 months and new brain metastasis 16 10 Confluent maculopapular eruption (thighs and upper arms) Superficial perivascular dermatitis with occasional eosinophils (DHR) Topical triamcinolone Quiescent/well‐controlled
#7 49 Male Metastatic melanoma NRAS Q61R pan‐RAF inhibitor (LXH254) + ERK inhibitor (LTT462) AWD after 42 months and new jejunum metastasis 56 5

Eruptive dark macules (thighs)

Background of hypopigmented patches secondary to prior immunotherapy

 Moderate to severe dysplastic nevi Monitor No new eruption
#8 69 Male Metastatic melanoma NRAS Q61K pan‐RAF inhibitor (LXH254) + Trametinib AWD after 5 months with partial response according to imaging 8 2–4 Acneiform eruption with multiple papules and pustules (chest and back) that evolved to diffuse erythema with exfoliative/erythema Subcorneal collection of neutrophils, mild spongiosis with eosinophils consistent with AGEP‐like reaction Topical traimcinolone and PO doxycycline; PO prednisone Well‐controlled
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Abbreviations: AGEP, acute generalized exanthematous pustulosis; AWD, alive with disease; DHR, dermal hypersensitivity reaction; DOD, died of disease; PO, by mouth.

DTs of pan‐RAF/RAS inhibitors included acneiform eruption (Patients 1, 3, 4, 5, and 8), which was complicated by ulcerations after 2–3 months in Patient 3, flaccid vesicles in Patient 4, and exfoliative erythroderma in Patient 8. In the remaining patients, DTs also included purpuric patches and papules in Patient 2, maculopapular eruption in Patient 6, and eruptive dark nevi in Patient 7 (Table 1). Representative clinical photos (Patients 4 and 5) are shown in Figure 1.

FIGURE 1.

FIGURE 1

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Representative clinical photos. Patient #5 who presented with multiple papules and pustules on head, trunk and extremities (A) and Patient #4 who presented with multiple papules and pustules on scalp that evolved to crusted erosion, flaccid vesicles, and papules on hands and shins (B).

Biopsy examination of the pan‐RAS/RAF inhibitor–associated DTs revealed suppurative folliculitis (Patients 1 and 5) and perivascular dermatitis (dermal hypersensitivity reaction [DHR]; Patients 2 and 6) as the two most frequent histopathological patterns biopsied. Biopsies of the suppurative folliculitis consisted of dilated hair follicles packed with numerous neutrophils and perifollicular neutrophilic infiltrate (Figure 2). Biopsies of the DHR histopathologically exhibited a superficial perivascular lymphohistiocytic infiltrate with occasional eosinophils (Figure 3). The biopsy for Patient 3 exhibited a sparse inflammatory infiltrate, scale crust, and a few neutrophils secondary to the ulcer (Figure 4). Multiple deeper sections were examined and a suppurative folliculitis was not observed. The skin biopsy for Patient 4 demonstrated spongiosis and a subcorneal blister with acantholysis and an associated superficial perivascular lymphocytic infiltrate with scattered neutrophils and eosinophils (Figure 5). The histopathologic features were suggestive of a drug‐induced pemphigus foliaceous (PF)‐like reaction; however, immunofluorescence and serologic studies were not available. The skin biopsy for Patient 7, who had eruptive dark macules, demonstrated biopsies of multiple dysplastic nevi with moderate to severe architecture disorder and moderate cytologic atypia (Figure 6). Immunohistochemical studies performed on the melanocytic nevi using a pan‐melanocytic cocktail and SOX10 antibodies highlighted melanocytic proliferation in the epidermis (Figure 6). A skin biopsy for Patient 8 demonstrated spongiotic dermatitis with focal clusters of subcorneal neutrophils and perivascular lymphohistiocytic infiltrate with eosinophils (Figure 7). A diagnosis of acute generalized exanthematous pustulosis (AGEP) was considered in the context of treatment with a pan‐RAF inhibitor.

FIGURE 2.

FIGURE 2

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Acneiform dermatologic toxicity associated with pan‐RAS/RAF inhibitors. Histopathologic examination revealed a suppurative folliculitis with dense neutrophilic inflammation of the follicle (Patient #1 and #5, A and C, respectively, hematoxylin and eosin [H&E], ×20), with follicular dilation and disruption (Patient #1 and #5, B and D, respectively, H&E, ×100).

FIGURE 3.

FIGURE 3

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Dermal hypersensitivity reaction (DHR) associated with pan‐RAS/RAF inhibitors. Histopathologic examination revealed superficial perivascular lymphohistiocytic infiltrate with occasional eosinophils (Patient #2 and #6, A and C, respectively, hematoxylin and eosin [H&E], ×40; B and D, H&E, ×400). In addition, Patient #2 also showed numerous extravasated erythrocytes, consistent with dermal purpura (B, H&E, ×400).

FIGURE 4.

FIGURE 4

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Nonspecific cutaneous ulceration associated with pan‐RAS inhibitors. Histopathologic examination revealed scale crust, ulceration, and sparse inflammation (Patient #3. A, hematoxylin and eosin [H&E], ×100) with few neutrophils secondary to ulcer. (B, H&E, ×200).

FIGURE 5.

FIGURE 5

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Pemphigus foliaceous (PF)‐like dermatologic toxicities associated with pan‐RAS inhibitor. Histopathologic examination revealed subcorneal blister with acantholysis and PF‐like features (Patient #4. A, hematoxylin and eosin [H&E], ×20; B, H&E ×400).

FIGURE 6.

FIGURE 6

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Eruptive dysplastic nevi associated with pan‐RAF inhibitors. Histopathologic examination of a representative lesion revealed junctional dysplastic nevi with moderate to severe architectural disorder atypia and moderate cytologic (Patient #7. A, hematoxylin and eosin [H&E], ×20, B, H&E, ×100). Immunohistochemical study with pan‐melanocytic cocktail (HMB‐45 and antityrosinase) highlights the melanocytic proliferation without confluency or upward pagetoid migration (B, ×100).

FIGURE 7.

FIGURE 7

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Acute generalized exanthematous pustulosis (AGEP)‐like dermatologic toxicities associated with pan‐RAF inhibitors. Histopathologic examination revealed subcorneal collections of neutrophils with AGEP‐like features with associated dermal lymphocytic infiltrate with eosinophils (Patient #8. A, hematoxylin and eosin [H&E], ×20; B, H&E, ×200).

Management of the DTs included topical and/or systemic steroids, antimicrobials, and retinoids. Six of the eight patients were alive with disease after 5–42 months of initiation of pan‐RAF/RAS inhibitor therapy, whereas two patients had died of disease.

4. Discussion

The clinical and histopathologic features of pan‐RAS/RAF associated DTs in our cohort of patients were primarily inflammatory except for one patient who developed eruptive nevi during therapy. Acneiform and maculopapular eruptions and patches were the typical clinical presentations with acneiform eruption (onset of rash approximately 1–8 weeks) as the initial clinical presentation in five patients treated with pan‐RAF/RAS inhibitor. The histopathologic features displayed more variation as lesions were biopsied at different time points and as the DTs evolved in some patients. Histopathologic features of a suppurative folliculitis and DHR correlated with the clinical features of acneiform and maculopapular eruptions, respectively. A recent study reported five acneiform and papulo‐pustular rashes in melanoma patients treated with pan‐RAF inhibitors, two of which were biopsied with histological findings of folliculitis similar to the current case series [10]. The onset of acneiform eruption in the previously published report occurred at approximately 1–2 weeks from initiation of therapy [10]. In general, the onset of acneiform eruption to pan‐RAF/RAS inhibitors appears to occur early during therapy. In addition, a subset of patients in this report with acneiform eruption may exhibit multiple morphologic types DT with different clinical and histopathologic features. Thus, close clinical monitoring is essential.

DHR is one of the least specific, off‐target DTs that can occur not only in Nibs but also with various types of medications. In contrast, acneiform eruption is a common on‐target reaction to Nib therapies that block EGFR and MAPK/mammalian target of rapamycin (mTOR) signaling pathways, respectively [9, 11, 12, 13].

EGFR signaling is an important mediator in keratinocyte differentiation, skin barrier function, and maintenance of the cutaneous immune‐homeostasis. Disruption of EGFR signaling and impaired keratinocyte differentiation promotes a pro‐inflammatory response and impaired skin barrier function that results in the development of acneiform eruption in patients treated with EGFR inhibitor therapy [14, 15]. There is also evidence showing EGFR signaling exerts a controlling role in ERK signaling; thus, Nibs that target MAPK (e.g., pan‐RAS/RAF inhibitors) disrupts downstream signaling of keratinocyte differentiation and altered skin barrier function resulting in an altered cutaneous immune‐homeostasis and development of acneiform eruption that may be exacerbated by commensal microbiota [16].

Other off‐target DTs include bullous pemphigoid in patients treated with Nibs, but it is extremely rare (reported in < 1%) [9, 17, 18, 19, 20]. To the best of our knowledge, pemphigus foliaceous‐like reactions are not typical DTs from Nibs involving the MAPK pathway. Severe cutaneous adverse reactions (i.e., Stevens–Johnson syndrome/toxic epidermal necrolysis), drug rash with eosinophilia and systemic symptoms (DRESS), and AGEP, although uncommon, have rarely been reported with Nibs [9, 21, 22].

DTs have been classified into five main categories: inflammatory, immunobullous, keratinocytic and melanocytic reactions, and cutaneous deposits [9, 17]. While BRAF inhibitors are commonly associated with maculopapular rash or phototoxicity and the EGFR inhibitors are more commonly associated with acneiform eruption, eczema or paronychia, the inflammatory DTs can have shared features among Nibs that involve the MAPK pathway at different levels [9, 23, 24]. Interestingly, a small subset of patients treated with pan‐RAS inhibitor developed multiple morphologic forms of DT. Multiple cutaneous types of DT from immune checkpoint and BRAF inhibitors are known to rarely occur [9, 13]. Whereas inflammatory reactions represent the most common type of DTs for all categories of Nibs, keratinocytic reactions such as squamous cell carcinomas, keratoacanthomas, and verrucae are more unique to Nibs targeting BRAF, resulting from the paradoxical MAPK activation of BRAF wild‐type keratinocytes [25, 26, 27]. Similarly, BRAF wild‐type melanocytes can be paradoxically activated, resulting in eruptive nevi and, rarely, melanoma after treatment with BRAF Nibs [25, 28, 29]. Keratinocytic reactions were not observed in this small cohort of patients treated with pan‐RAF inhibitor; however, one patient did develop eruptive nevi during pan‐RAF inhibitor therapy [30, 31, 32, 33].

This study is limited by its relatively small sample size in a single academic institution. The patients that were biopsied during treatment may only represent a subset of all those who experienced DTs. Severe DT have low incidence and require a much larger cohort to capture those rare events. Two patients in the study exhibited histopathologic features suggestive of PF‐like and AGEP adverse reactions. Future study to include more patients on pan‐RAS/RAF inhibitors in multicenter settings with complete workup will be helpful to better understand the DT profiles of the pan‐RAS/RAF inhibitors.

5. Conclusions

The DTs of the novel pan‐RAS/RAF inhibitors in this study were categorized primarily as inflammatory, with reaction on melanocytes observed in one patient. Disruption of the MAPK pathway with pan‐RAS/RAF inhibitors shows an overlap of DTs seen with other Nibs that target the MAPK pathway.

Ethics Statement

This case report was conducted in accordance with the ethical principles of University of Texas—MD Anderson Cancer Center.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

We acknowledge Donald Norwood in the Department of Scientific. Publications at MD Anderson Cancer Center for his editorial review. We thank Ms. Kim‐Anh Vu, in the Department of Pathology at MD Anderson Cancer Center for her assistance in the preparation of figures.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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