HSP-90

[rick1981]

Andere drug genoemd door Dr. Flaherty, kan mogelijk BRAF resistentie vertragen/voorkomen:

Inhibition of HSP90 by AT13387 Delays the Emergence of Resistance to BRAF Inhibitors and Overcomes Resistance to Dual BRAF and MEK Inhibition in Melanoma Models.

Smyth T1, Paraiso KH2, Hearn K1, Rodriguez-Lopez AM1, Munck JM1, Haarberg HE2, Sondak VK3, Thompson NT1, Azab M4, Lyons JF1, Smalley KS5, Wallis NG6.



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Abstract

Emergence of clinical resistance to BRAF inhibitors, alone or in combination with MEK inhibitors, limits clinical responses in melanoma. Inhibiting HSP90 offers an approach to simultaneously interfere with multiple resistance mechanisms. Using the HSP90 inhibitor AT13387, which is currently in clinical trials, we investigated the potential of HSP90 inhibition to overcome or delay the emergence of resistance to these kinase inhibitors in melanoma models. In vitro, treating vemurafenib-sensitive cells (A375 or SK-MEL-28) with a combination of AT13387 and vemurafenib prevented colony growth under conditions in which vemurafenib treatment alone generated resistant colonies. In vivo, when AT13387 was combined with vemurafenib in a SK-MEL-28, vemurafenib-sensitive model, no regrowth of tumors was observed over 5 months, although 2 of 7 tumors in the vemurafenib monotherapy group relapsed in this time. Together, these data suggest that the combination of these agents can delay the emergence of resistance. Cell lines with acquired vemurafenib resistance, derived from these models (A375R and SK-MEL-28R) were also sensitive to HSP90 inhibitor treatment; key clients were depleted, apoptosis was induced, and growth in 3D culture was inhibited. Similar effects were observed in cell lines with acquired resistance to both BRAF and MEK inhibitors (SK-MEL-28RR, WM164RR, and 1205LuRR). These data suggest that treatment with an HSP90 inhibitor, such as AT13387, is a potential approach for combating resistance to BRAF and MEK inhibition in melanoma. Moreover, frontline combination of these agents with an HSP90 inhibitor could delay the emergence of resistance, providing a strong rationale for clinical investigation of such combinations in BRAF-mutated melanoma. Mol Cancer Ther; 13(12); 2793-804. ©2014 AACR.

[Paladium]

Voor zover ik begrijp heeft men sterke aanwijzingen dat HSP90 (heat shock protein 90) een belangrijke rol speelt in het goed en robuust functioneren van de gemuteerde mogelijk tot kankergroei signalerende (oproepende) proteïnen zoals die in tumoren worden aangetroffen.

In onderstaande afbeelding is te zien hoe in de bovenste route het mogelijk tot kankergroei aanzettende proteïne (geel aan de linkerzijde, b.v. BRAF) door een verbinding met HSP90 (blauw) tot activatie komt of kan komen. Dit is dan eventueel zichtbaar als proliferatie (een snelle vermeerdering) en een hogere overlevingsgraad op celnivo.

Via de onderste route wordt door het gebruik van een HSP90 inhibitor (oranje blokje) voorkomen dat het mogelijk tot kankergroei aanzettende proteïne een verbinding aangaat met HSP90. Het proteïne komt niet tot activatie en sterft hopelijk een ellendige dood