Identification of Mechanism of Resistance to Current Melanoma Therapy

Neel Fofaria, PhD candidate at Texas Tech University, talked on “Identification of Mechanism of Resistance to Current Melanoma Therapy” at www.bio2devicegroup.org event.

Melanoma is a devastating form of skin cancer that begins in melanocytes, or pigment containing cells in the skin.  It is not restricted to the skin but also occurs in eyes and intestinal mucosa.  Mutation of BRAF gene is implicated in 40-60% of melanoma development. This mutation is believed to activate mitogen-activated protein kinase (MAPK) pathway and BRAF has been validated as an important target, said Fofaria.

The mitogen-activated protein kinase (MAPK) pathway, designed and donated to Wikpedia by Abgent, graphic execution by User:kosigrim (Photo credit: Wikipedia)

Vemurafenib (marketed as Zelboraf) is a commonly prescribed treatment for advanced metastatic melanoma. However, only about 50% of cancers with BRAF mutation, respond to this line of therapy.  Resistance to apoptosis is a common challenge in many malignancies that result is both aggressive progress of the cancer and resistance to conventional regimens.  Certain abnormalities in a variety of intrinsic and extrinsic molecular mechanisms of the cell lines that promote the tumor formation have lately generated a lot of focus.  Mcl-1 from a family of Bcl-2 proteins, has been implicated in aggressive melanoma that does not respond to traditional therapy.  Mcl-1 is a highly expressed pro-survival protein in these cancers.

English: Structure of the BRAF protein. Based on PyMOL rendering of PDB 1uwh. (Photo credit: Wikipedia)

Studies have indicated that Vemurafenib treatment induces Mcl-1 expression in certain melanoma cells, said Fofaria.  Vemurafenib is an effective line of treatment in about 50% patients with certain BRAF mutation, but in others the drug stimulates normal BRAF and possibly promotes tumor growth.  Fofaria shared that studies at their lab at Texas Tech indicated this to be the case.  Therefore, they further hypothesized that combination targeted therapy with Vemurafenib and Mcl-1 inhibitor (like TW-37), might overcome this resistance and lead to a better outcome.  

This was confirmed in several studies.  Combination targeted therapy of Mcl-1 inhibitor (TW-37) and Vemurafenib increased apoptosis and resistance to Vemurafenib was overcome with this combination.  Additionally, involvement of Mcl-1 was confirmed in the resistance to the recent FDA approved combination of Dabrafenib (BRAF inhibitor) and Trametinib (MEK1/2 inhibitor).  Further studies confirmed that only Mcl-1 was playing a crucial role and no other protein was implicated in a signficant subset of resistant tumors.  Additionally, TW-37 is a small molecule, can be easily administered orally, and was found to be safe in mice studies.  These results were further confirmed in patient tumor biopsy samples obtained from collaboration with Mass General, said Fofaria.

Indeed, one size fits all is no more a workable solution in case of malady like cancer.  Administering more personalized medicine and combining agents that target different mechanisms in divergent cancers, may be the way of the future.  The talk was followed by Q&A.