Paradoxical Oncogenic Transformation
Long-term effects of BRAF inhibition
The use of BRAF inhibitors in the clinic is expanding. However, secondary skin changes, including hyperkeratosis, keratoacanthomas and squamous-cell carcinomas, can occur. Secondary melanomas, gastric and colonic polyps and recurrences of pre-existing malignancies have also been reported. Strategies to manage or limit the development of treatment-induced cancers include combination therapy with inhibitors of BRAF and MEK, and use of retinoids, topical 5-fluorouracil and cyclooxygenase-2 inhibitors wrote Dr Geoffrey Gibney and colleagues from the Moffitt Cancer Center and Research Institute, Tampa (USA) in the review article published in the July issue of Nature Reviews Clinical Oncology.
The authors described in their article the clinical and mechanistic manifestations of secondary cancers that have thus far been observed to arise as a consequence of BRAF inhibition. They discuss the concept of pre-existing populations of partly transformed cells with malignant potential that might be present in various organ systems, and the rationale for novel therapeutic strategies for the management of BRAF-inhibitor-induced neoplasia.
Selective BRAF inhibitors provide clear clinical benefit to patients with advanced BRAF-mutant melanoma. The major off-target effects of this drug class are associated with the paradoxical activation of the MAPK pathway, leading to the development of secondary malignancies. Although cutaneous squamous-cell carcinomas are the best-documented, the emergence of other (non-keratinocyte) secondary tumours is a growing concern. Although the significance of the colonic and gastric polyps associated with chronic BRAF-inhibitor therapy is still unclear, questions remain over whether these lesions will eventually undergo malignant transformation.
Long-term follow-up studies and surveillance will be necessary to determine the actual incidence of these events and whether specific screening procedures are warranted for patients undergoing therapy with BRAF inhibitors. As BRAF inhibitors are currently under investigation in the adjuvant setting for patients with resected stage II and III melanoma and are being explored in other BRAF-mutant malignancies, these considerations will become increasingly critical. Indeed, concerns of secondary malignancies have led to the exclusion of patients with a family history of colorectal carcinoma syndromes from the trial of adjuvant vemurafenib in those with resected cutaneous BRAF-mutant melanoma. Despite these concerns, the development of BRAF inhibitors represents a major milestone in the therapeutic management of advanced melanoma.
In most cases, paradoxical MAPK activation—resulting from the BRAF-inhibitor-mediated homodimerization and heterodimerization of nonmutant RAF isoforms—seems to underlie the development of these secondary tumours. Although evidence supports that therapy with the simultaneous administration of BRAF and MEK inhibitors abrogates the onset of treatment-induced squamous-cell carcinomas, whether combination treatment will limit the emergence of all BRAF-inhibitor-driven pathologies is unclear.
The authors of this review article performed a literature search of all records from PubMed on melanoma and BRAF inhibition published between 2002 and 2013. In addition, they searched on abstracts presented at the ASCO Annual Meetings, The Society for Melanoma Research Annual Meetings and the AACR Annual Meetings. In this news we focus on prevention of secondary cancers and insights gained on stimulation of growth of clinically occult, pre-existing mutant cells.
Preventing secondary malignancies
The authors speculated if the primary driver for secondary malignancies during BRAF-inhibitor therapy is the paradoxical activation of the MAPK pathway, a practical approach to prevent these events is concurrent downstream inhibition of either MEK or ERK. Indeed, in the phase I–II study of dabrafenib and trametinib in patients with BRAF-mutant melanoma, the number of patients who developed squamous-cell carcinomas was lower in the combination arms (5%) than in the dabrafenib monotherapy arm (19%). The results from the ongoing phase III trial of dabrafenib plus trametinib versus single-agent dabrafenib (Combi-D) or single-agent vemurafenib (Combi-V) will help determine if concurrent MEK inhibition is an effective strategy for preventing squamous-cell carcinomas and, possibly, other secondary malignancies. However, this strategy is unlikely to resolve the issue completely. The cutaneous squamous-cell carcinomas still can occur in patients taking concurrent BRAF and MEK inhibitors, and recurrent KRAS-mutant colorectal cancer was noted in a patient on dabrafenib plus trametinib combination therapy.
An alternative approach to prevent paradoxical activation of the MAPK pathway might be through the use of a new class of pan-RAF inhibitors, so-called paradox breakers. These agents, exemplified by the compound PB04 (PLX7904), were empirically selected for their lack of paradoxical MAPK activation in NRAS-mutant melanoma cells, despite retaining the ability to potently block the signalling of phosphorylated ERK in BRAF-mutant melanoma cells. Studies have shown that the paradox breakers are pro-apoptotic and inhibit the anchorage-independent growth of melanoma cell lines in which acquired resistance to the compound PLX4720 is mediated through mutant NRASQ61K. Further studies will be required to determine if these agents have similar activity to the BRAF and MEK inhibitor combination in preventing the onset of HRAS-mutant squamous-cell carcinomas and keratoacanthomas.
In addition to strategies targeting the MAPK pathway, a case report has demonstrated efficacy of the synthetic retinoid acitretin in the management of vemurafenib-induced hyperkeratotic papules and cutaneous squamous-cell carcinomas. Indeed, topical and systemic retinoids have been used for various dermatological conditions and have shown efficacy in the prevention of non-melanoma skin cancers in solid-organ transplant recipients taking immunosuppressive agents. These retinoids activate the retinoic acid receptor to regulate gene transcription, ultimately promoting cell maturation and differentiation, as well as decreasing cell growth and malignant transformation. As retinoid administration can be associated with substantial toxicity, further prospective evaluation will be necessary before this treatment strategy is recommended for general patient care.
Similar to the use of retinoids, inhibition of cyclooxygenase (COX)-2 has been evaluated as a strategy to prevent BRAF-inhibitor-mediated squamous-cell carcinomas development. Experimental and preclinical investigations of squamous-cell carcinomas carcinogenesis induced by ultraviolet light have shown the increase in COX-2 expression and prostaglandin production can be abrogated by the use of the COX-2 inhibitors, such as celecoxib and diclofenac, mitigating squamous-cell carcinomas development. In patients with chronic ultraviolet-radiation-mediated skin damage, oral celecoxib (200 mg twice daily) was shown to be an effective chemopreventive strategy to reduce squamous-cell carcinomas development.
Importantly, COX-2 inhibition with celecoxib has also been explored as a strategy to reduce the development of colorectal adenomas in individuals at high risk for colorectal polyps or cancers, showing a modest reduction in adenomas detected on colonoscopy. Indeed, mouse-model experiments suggest that celecoxib treatment delays the onset of squamous-cell carcinomas development that is mediated by DBMA, TPA and PLX4720, reducing the eventual tumour burden by >90%. Whether this regimen could be effective and safe in patients receiving selective BRAF inhibitors remains to be determined.
The ability of BRAF-kinase inhibitors to stimulate the growth of clinically occult, pre-existing mutant cells that have been dormant can provide important new insights into the process of oncogenic transformation. As individuals age, their prolonged exposure to environmental carcinogens increases the likelihood of acquiring potentially deleterious mutations in cells. Most of these will never undergo full oncogenic transformation and are destined to remain in an initiated—but growth-arrested—state throughout the lifetime of the individual. In normal sun-exposed skin, keratinocyte clones can be readily identified that harbour persistent oncogenicTP53mutations.
The data to date suggest that, in situations where paradoxical activation of the MAPK pathway as a consequence of selective BRAF inhibition occurs, an oncogenic event might 'awaken' pre-existing mutant cells within the body. Although thousands of patients have now received BRAF-inhibitor therapy, these drugs have mostly been used in individuals with advanced-stage melanoma. As long-term follow-up data are often lacking for this group of patients, it is currently difficult to judge the full spectrum of potential secondary malignancies that can occur in patients on BRAF-inhibitor therapy. Depending on the results of ongoing trials, single-agent BRAF inhibition might well be superseded by BRAF and MEK inhibitor combination. The ability of this combination to abrogate paradoxical MAPK activation is expected to reduce the incidence of secondary malignancies, but might not entirely prevent it.
The corresponding author, Dr Keiran Smalley is supported by NIH/National Cancer Institute grants (R01 CA161107-02 and U54 CA143970-03).
Dr Gibney acts as a consultant or advisory board member for Genetech and Roche. All other authors declare no conflict of interest.
Gibney GT, Messina JL, Fedorenko IV,et al. Paradoxical oncogenesis – The long-term effects of BRAF inhibition in melanoma. Nature Rev Clin Onc 2013; 10: 390-399.
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