Melanoma treatment adds a new target: endogenous DOPA can inhibit melanoma by inhibiting CHRM1 signaling pathway

Melanoma is the deadliest form of skin cancer

Melanoma develops from melanocytes (MCs), which are normally located in the basal layer of the skin and hair follicles and produce the melanin pigment, the primary determinant of skin and hair color

Primary LMCs and DMCs were engineered using lentiviruses to express mutant oncoproteins associated with spontaneous human melanoma by analyzing dark melanocytes (DMCs) and light melanocytes (LMCs) from the foreskin of newborn infants, Oncoprotein-transduced DMCs were found to grow two-fold slower and maintain a more differentiated state than similarly treated LMCs, and engineered skins constructed from them were transplanted into immunodeficient mice (SCID) and cultured and found that tissues with lightly pigmented heMel cells In contrast to the formation of early-stage melanomas with large proliferative melanocyte nests that have hallmark melanoma features, dark heMel cells do not, although single dark heMel cells are present in the basal layer of the epidermis The development of melanoma suggests that DMC is resistant to BRAF-driven transformation, independent of UVR

Melanin is synthesized through a complex multistep process involving sequential oxidation and polymerization of tyrosine and is regulated by more than 200 different genes

Dopa inhibits MC proliferation in vitro and in vivo and melanoma

The researchers treated multiple human and mouse melanoma cell lines with dopa/carbidopa and observed that this treatment significantly inhibited the proliferation of most, but not all, melanoma cell lines, regardless of BRAF and NRAS mutation status

So might DOPA have therapeutic utility as a systemically delivered drug for melanoma in vivo? Systemic administration of combined levodopa and carbidopa has been approved by the Food and Drug Administration (FDA) for the treatment of Parkinson's disease

The authors further used high-throughput pharmacology and genetic in vivo CRISPR screens to determine that DOPA restricts melanocyte and melanoma cell proliferation (CHRM1) signaling by inhibiting the muscarinic acetylcholine receptor M1