E74c Rapidly renewing tissues: skin/melanoma

Topic

Melanoma has the highest mutation rate of all solid tumors, a rate driven primarily by the cumulative skin damage caused by the sun's ultraviolet radiation over the years. As a result of this cumulative exposure, melanoma acquires an extraordinarily high total mutational burden—far exceeding that of almost any other solid tumor.

At the same time, the skin is an organ subject to intense immune system surveillance due to its superficial and exposed location. This combination—an extraordinarily high mutational burden (resulting in numerous abnormal proteins recognizable by the immune system) coupled with the skin's intense immune surveillance—makes melanoma the solid tumor that responds best to immune checkpoint inhibitor immunotherapy; long-term, durable response rates with these drugs, whether used alone or in combination, reach nearly half of all treated patients.

The primary molecular driver of melanoma is a specific mutation in a gene that normally regulates cell growth—a mutation present in approximately half of all melanoma cases. This mutation keeps the gene's intracellular chemical signaling pathway permanently active; normally, this pathway is activated only by growth factor signals originating outside the cell. By remaining permanently active, the pathway drives tumor cell proliferation independently of any external growth signals.

Inhibitor drugs exist that specifically target this mutated gene and the signaling pathway it keeps active; these inhibitors demonstrate high initial efficacy in halting melanoma growth. However, resistance to these inhibitor drugs is nearly universal: almost all patients eventually develop resistance to the treatment because clones of resistant tumor cells rapidly emerge within the tumor, selected precisely by the pressure the inhibitor drug itself exerts on the tumor.

It is this dual nature of melanoma—an extraordinarily high mutational burden that makes it highly visible to the immune system and highly responsive to immunotherapy, yet which also includes, in half of all cases, a driver mutation capable of autonomously sustaining tumor growth and generating near-universal resistance to drugs targeting it—that explains why melanoma is simultaneously one of the solid tumors that responds best to immunotherapy and one that most rapidly develops resistance to targeted therapy.

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