Precision therapies, although effective in earlier stages, may not work later.
In a recent study from the UCLA Jonsson Comprehensive Cancer Center, investigators analyzed genetic and transcriptomic changes in metastatic organs and tumor macroenvironment of recently deceased patients with melanoma who responded initially to MAPK inhibitors (MAPKi) and immune checkpoint blockade (ICB) therapies but later died due to acquired resistance. The researchers looked to understand how cutaneous melanoma progresses after initial responsiveness to targeted therapy. The findings indicate MAPKi and ICB are respective contributors to gene amplification and deletion, facilitating therapy resistance in patients.1
“The findings from this study suggest potential new avenues for therapeutic interventions. These could aim at overcoming therapy resistance by targeting identified DNA repair pathways and immune evasion mechanisms,” said Wael Harb, MD, a hematologist and medical oncologist at MemorialCare Cancer Institute in Fountain Valley, California, and vice president for medical affairs at Syneos Health. “The study provides a foundation for developing more personalized, effective treatment strategies for metastatic melanoma.”
Current knowledge about the mutational landscape and treatment of cutaneous melanoma mostly comes from treatment-naïve patients or those with early-stage disease when cancer has not overtly spread. The authors highlighted that previous studies did not focus on treatment effects of MAPKi and ICB on the mutational landscape of the tumors. Monitoring and therapeutic strategies to counter resistance require in-depth insights into multiorgan mechanisms and disease heterogeneity. For this reason, the present study focused on warm autopsies from patients with metastatic and terminal diseases to understand how these cancers evade powerful therapies.1
“Warm autopsies were used to gain a unique, in-depth perspective of metastatic cutaneous melanoma that affects various organs,” Harb said. “This method allows researchers to understand the complex mechanisms of disease progression and therapy resistance in a real-world context, beyond what can be discerned from living subjects or conventional biopsies.”
Melanoma is one of the most aggressive cancers worldwide and fifth most common in the United States.2 According to the American Cancer Society, approximately 100,000 new cases of melanoma will be diagnosed in the United States in 2023.3 Although melanoma accounts for about 1% of all cutaneous tumors diagnosed in the United States, it is the leading cause of skin cancer–related deaths.2
Targeted therapies have had a tremendous impact in managing metastatic melanoma. Targeted therapies are less toxic and more efficacious than traditional therapies; however, they are less effective after prolonged treatment due to acquired resistance caused by mutations and the activation of alternative mechanisms in melanoma tumors.4 Although MAPKi and ICB have become standard-of-care treatment strategies for patients with metastatic cutaneous melanoma in developed countries, clinical relapse occurs frequently, with therapy resistance becoming highly lethal. The authors also noted that the evolution of MAPKi (vs ICB) resistance shifts the mutational signatures, implicating therapy-elicited DNA damage and/or deficiency in repair pathways as culprits.1
“Precision therapies, although effective in earlier stages, may not work in later stages due to the complexity of the disease state that arises from accumulated genetic alterations, adaptation of cancer cells, and evolution of resistance mechanisms,” Harb said. “These make the cancer less responsive to therapies that were initially effective, leading to treatment failure.”
Research reveals that metastasis and therapy failure are among the most common causes of death in patients with melanoma.1 Acquired therapy resistance coevolves with and may also promote metastatic progression.
“Metastasis in melanoma is driven by a complex interplay of factors, including genetic alterations, structural variants, and interactions with organspecific environments,” Harb said. “These interactions ultimately result in immune system changes that foster metastasis and resistance to therapies, leading to the progression of the disease.”
Structural variants and chromothripsis represent a major source of aberrations in melanoma genomes. Research suggests that chromothripsis, a phenomenon characterized by massive genomic rearrangements, contributes to oncogene amplification and may be a major factor driving genomic evolution in human cancer. A comprehensive analysis of human cancers found evidence of chromothripsis in more than 50% of melanoma cases.5
Potential Therapeutic Targets and Alternative Strategies
A study published in Cancers reviewed the contribution of microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) in melanoma invasion and metastasis. The study revealed that therapeutic strategies aimed at modulating lncRNAs combined with targeted agents and/or immunotherapy might be a more effective solution, considering that miRNAs and lncRNAs are not only involved in melanoma invasion and metastasis but also facilitate resistance against available molecular treatment approaches.6
Another study published in Cancer Discovery suggests that blocking cancer genomic instability may prevent tumor metastasis and acquired resistance. The study pointed out that targeting DNA-PKCS/nonhomologous end-joining genes may prevent resistance in MAPKi-treated melanomas.7 However, one study reported MYC amplifications at the lesion level in ICI-resistant patients, and another study published in Nature Genetics found that pharmacological inhibition of downstream effectors of RAC1 signaling could therapeutically benefit sun-exposed melanoma.8,9
The literature identifies various mechanisms of resistance and metastasis, guiding the development of new, targeted treatments. Focusing on these specific genetic and microenvironment changes allows the potential to create more effective therapies for patients with advanced metastatic melanoma.
Regarding developments for therapeutic strategies, the current study’s authors highlighted organ-specific metastatic signatures that characterize therapy-resistant melanoma as a potential therapeutic target. For instance, liver and spleen metastases show neural differentiation, whereas melanoma brain metastasis displays signatures of IFN signaling, oxidative phosphorylation, and PI3K/AKT signaling, which the study authors suggest as therapeutic targets.1
The study also noted that cutaneous melanomas strongly display an immune desert but CD8+ macrophage-biased archetype with enrichment of T-cell exhaustion. For melanoma brain metastasis, loss of antigen presentation and enrichment of type 2 immunity suggest TGFβ blockade and upregulation of cytotoxic natural killer cell-mediated or CD4+ T-cell–mediated antitumor immunity as potential therapeutic strategies.1 Further, alternative strategies for treatment development may include targeting DNA repair pathways to exploit cancer cells’ vulnerabilities, counteracting immune evasion to induce the immune response against the tumor, manipulating the tumor microenvironment to make it less conducive to tumor growth, and developing precision therapies on the basis of individual genetic alterations and disease characteristics.
“The study [from UCLA] is limited by a relatively small sample size and the need for further validation of the findings in larger, more diverse patient cohorts. Moving forward, it would be important to validate these findings in larger cohorts, encompassing diverse samples, including various subtypes of melanoma and ethnic backgrounds,” Harb said. “The potential therapeutic strategies suggested by this study should be further explored in preclinical models and clinical trials to evaluate their efficacy.”
About the Author
Fazila Rajab, BDS, is a freelance medical writer and editor working with MJH Life Sciences and the Society of Gynecologic Oncology.