A new study led by researchers at\u00a0The University of Texas MD\u202fAnderson Cancer Center\u00a0has\u00a0identified\u00a0a\u00a0way to tailor\u00a0drug\u00a0combinations based on specific tumor biology\u00a0to\u00a0improve outcomes\u00a0for\u00a0treatment-resistant\u00a0advanced\u00a0melanoma.\u00a0<\/p>\n
In preclinical models\u00a0from patients\u00a0with treatment-resistant tumors,\u00a0combining\u00a0standard BRAF and MEK inhibitors with\u00a0a\u00a0drug to block\u00a0proteins in the BCL2 family\u00a0\u2013\u00a0which drive tumor growth\u00a0\u2013\u00a0induced tumor regression\u00a0in a molecularly defined subset of resistant tumors, suggesting a path toward biomarker<\/a>-guided therapy.\u00a0<\/p>\n The study, published in\u00a0Nature\u00a0Communications, was led by\u00a0Vashisht Gopal\u00a0Yennu\u00a0Nanda, Ph.D., associate professor of\u00a0Melanoma Medical Oncology\u00a0and\u00a0Translational Molecular Pathology, in collaboration with senior author\u00a0Michael A. Davies, M.D., Ph.D., chair of Melanoma Medical Oncology.\u00a0<\/p>\n “Targeted therapy works by shutting down the main signal driving melanoma growth, but tumors often have backup systems that keep them alive,”\u00a0Yennu\u00a0Nanda\u00a0said. “By identifying which\u00a0protein\u00a0a tumor relies on for survival, we may be able to match patients to\u00a0drug\u00a0combinations\u00a0tailored to\u00a0their specific tumor biology.”\u00a0<\/p>\n Why do certain melanomas<\/a> become treatment-resistant?\u00a0<\/p>\n Approximately\u00a0half\u00a0of all melanomas carry a mutation<\/a> in\u00a0the\u00a0BRAF\u00a0gene, which\u00a0drives uncontrolled tumor growth. For\u00a0nearly a\u00a0decade,\u00a0the standard of care for these patients has been a combination of BRAF and MEK inhibitors, which\u00a0initially works for most patients.\u00a0However,\u00a0roughly 80%\u00a0of patients\u00a0develop\u00a0acquired\u00a0resistance and disease progression within two years,\u00a0potentially\u00a0due to an increase in certain proteins\u00a0within the BCL2 family.\u00a0<\/p>\n Cancer cells\u00a0often evade therapy by increasing production of\u00a0“survival proteins”\u00a0in the BCL2 family\u00a0\u2013 usually\u00a0BCL2, BCL-xL, and MCL1.\u00a0The\u00a0researchers\u00a0confirmed that melanoma tumors\u00a0express\u00a0unusually\u00a0high levels\u00a0of these proteins compared with most other cancer types, and that levels of BCL2 increase in patients\u00a0following\u00a0BRAF-MEK inhibitor\u00a0therapies,\u00a0likely contributing\u00a0to treatment resistance.\u00a0<\/p>\n How does\u00a0blocking these “survival proteins” shrink tumors, and how\u00a0can\u00a0doctors know which\u00a0protein\u00a0to target?\u00a0<\/p>\n Using\u00a0a large collection\u00a0of patient-derived xenograft (PDX) models\u00a0established\u00a0from melanomas with\u00a0acquired\u00a0resistance to standard therapy,\u00a0the\u00a0researchers tested\u00a0the addition of\u00a0a\u00a0BCL2\u00a0inhibitor\u00a0(navitoclax or venetoclax) to the standard two-drug regimen. They\u00a0found\u00a0a\u00a0subset of\u00a0previously\u00a0resistant\u00a0tumors now regressed\u00a0with the new combination\u00a0in\u00a0these models.\u00a0<\/p>\n Tumors with high baseline levels of BCL2 tended to respond, while tumors with high\u00a0baseline\u00a0MCL1\u00a0expression\u00a0tended to resist. To confirm the role of MCL1,\u00a0the\u00a0researchers\u00a0artificially raised\u00a0its levels in tumor cells, which\u00a0induced\u00a0resistance\u00a0to the triple combination.\u00a0<\/p>\n For tumors that overproduce MCL1, the team tested an alternative regimen\u00a0by pairing BRAF-MEK inhibitors with an experimental MCL1\u00a0inhibitor\u00a0called AZD5991. In a high-MCL1\u00a0PDX\u00a0model, this combination produced complete tumor regression, with no detectable tumors at the end of the experiment.\u00a0<\/p>\n What has prevented MCL1 inhibitors from advancing in clinical practice?\u00a0<\/p>\n MCL1\u00a0inhibitors\u00a0previously\u00a0have\u00a0demonstrated\u00a0antitumor activity\u00a0but have\u00a0been associated with\u00a0heart-related side effects in early clinical trials, leading several studies to be paused or halted.\u00a0In this study, adding BRAF-MEK inhibitors\u00a0appeared to protect\u00a0heart cells from the damaging effects of the MCL1\u00a0inhibitor.\u00a0<\/p>\n In laboratory models, the MCL1\u00a0inhibitor\u00a0alone disrupted\u00a0cardiac cell\u00a0energy production and caused signs of damage.\u00a0Adding BRAF and MEK inhibitors\u00a0largely reversed\u00a0these effects,\u00a0potentially because\u00a0the MEK inhibitor\u00a0helped\u00a0restore energy production in heart cells that MCL1 inhibitors otherwise disrupt.\u00a0Further research is needed to\u00a0determine\u00a0whether\u00a0this protective effect translates to patients.\u00a0<\/p>\n “We did not\u00a0anticipate\u00a0that pairing these drugs would reduce MCL1 inhibitor toxicity,” Davies said. “If this finding\u00a0is\u00a0confirmed\u00a0in clinical trials, it could give a second life to a class of drugs that has struggled to\u00a0advance\u00a0through development. It\u00a0also\u00a0reinforces that the most effective combinations are those that\u00a0eliminate\u00a0cancer while sparing healthy tissue.”\u00a0<\/p>\n What’s\u00a0next for this research?\u00a0<\/p>\n These\u00a0findings\u00a0support the\u00a0design\u00a0of\u00a0biomarker-guided clinical trials that match patients\u00a0to drug combinations based on tumor BCL2 and MCL1 expression.\u00a0To further this research, the team is\u00a0analyzing samples from a recent randomized Phase\u00a02\u00a0clinical trial of dabrafenib,\u00a0trametinib\u00a0and navitoclax in\u00a0BRAF-mutant melanoma patients\u00a0to\u00a0determine\u00a0whether MCL1\u00a0expression\u00a0predicted\u00a0clinical response.\u00a0Additional\u00a0preclinical and translational studies will be needed to evaluate the safety of BRAF-MEK inhibitor and MCL1 inhibitor combinations before they can be\u00a0evaluated\u00a0in patients.\u00a0<\/p>\n “Patients whose melanoma has stopped responding to standard therapies currently have very few effective\u00a0treatment\u00a0options,”\u00a0Yennu\u00a0Nanda\u00a0said. “Our findings could help address this critical\u00a0need\u00a0for these patients by guiding clinicians toward combinations tailored to each individual’s\u00a0tumors.”\u00a0<\/p>\n Source:<\/p>\n University of Texas M. D. Anderson Cancer Center<\/a><\/p>\n Journal reference:<\/p>\n Vashisht Gopal,\u00a0Y. N., et al.\u00a0(2026) Personalized targeting of BCL2 family proteins overcomes acquired resistance to BRAF-MEK inhibitors in preclinical melanoma. Nature Communications. DOI: 10.1038\/s41467-026-74691-9.\u00a0https:\/\/www.nature.com\/articles\/s41467-026-74691-9<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"A new study led by researchers at\u00a0The University of Texas MD\u202fAnderson Cancer Center\u00a0has\u00a0identified\u00a0a\u00a0way to tailor\u00a0drug\u00a0combinations based on specific…\n","protected":false},"author":2,"featured_media":258107,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6],"tags":[6781,2534,1757,2862,227894,26948,111,139,69,6840,3035,17561,2859,1518,145,3422,6843],"class_list":["post-506563","post","type-post","status-publish","format-standard","has-post-thumbnail","category-technology","tag-biomarker","tag-cancer","tag-drugs","tag-heart","tag-mek-inhibitor","tag-melanoma","tag-new-zealand","tag-newzealand","tag-nz","tag-oncology","tag-ph","tag-preclinical","tag-protein","tag-research","tag-technology","tag-therapy","tag-tumor"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts\/506563","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/comments?post=506563"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts\/506563\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/media\/258107"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/media?parent=506563"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/categories?post=506563"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/tags?post=506563"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}