BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops.,Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity.,Here, we show that uniquely low BCL-XL expression in melanoma biases the pro-survival pool towards MCL1.,Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, driving profound tumour cell death that requires BAK/BAX, BIM and BMF, and inhibiting tumour growth in vivo.,Combination of ERK1/2 pathway inhibitors with BCL2/BCL-w/BCL-XL inhibitors is stronger in CRC, correlating with a low MCL1:BCL-XL ratio; indeed the MCL1:BCL-XL ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL2/BCL-w/BCL-XL inhibitors.,Finally, AZD5991 delays acquired BRAFi/MEKi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi + MEKi resistance.,Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes.,BRAF or MEK1/2 inhibitors are cytostatic in melanoma and the surviving cells develop drug resistance.,This study shows that the pro-survival pool is biased towards MCL1 in melanoma so that BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, improving tumour growth inhibition.
The prognostic significance of the width of the ulceration in primary melanomas remains unclear, and there is a relative paucity of data for lymphovascular invasion (LVI), microscopic satellitosis (MS), perineural invasion (PNI), and mitotic rate when compared with other pathological elements currently required for reporting.,To evaluate the prognostic importance of the ulceration width and other important pathologic measurements, a single‐institutional retrospective study was conducted using records of cutaneous melanoma patients who underwent sentinel lymph node (SLN) biopsy at The University of Texas, MD Anderson Cancer Center between 2003 and 2008.,We identified 1898 eligible patients with median tumor thickness of 1.25 mm and median follow‐up of 6.7 years.,By multivariable analyses, the strongest risk factor for SLN positivity was high tumor thickness followed by the presence of LVI.,The pathologic measures with the strongest influence on recurrence‐free survival (RFS) were tumor thickness and positive SLN status.,Ulceration width and presence of MS were also significantly associated with RFS while PNI was not.,Factors with the strongest influence on melanoma‐specific survival (MSS) were positive SLN status and mitotic rate.,In conclusion, SLN biopsy should probably be offered if the primary tumor has LVI.,MS is an adverse prognostic factor for RFS, but its influence on outcome is modest.,Ulceration width predicts RFS but loses its independent prognostic significance for MSS when adjusting for currently used clinicopathological factors.,In view of its impact on MSS, mitotic rate should be recorded for cutaneous invasive melanomas across all T categories.