Resistance to RET targeted therapy in Thyroid Cancer: Molecular basis and overcoming strategies.

Thyroid cancer is the most frequently diagnosed endocrine malignancy, with an increasing incidence over the last decades. The recent advances in understanding the molecular mechanisms underlying the carcinogenesis of thyroid cancer have led to a better therapeutic approach of these tumors. This has allowed the development and approval of several drugs during the past decade. The rearranged during transfection [RET] protooncogene encodes a transmembrane receptor tyrosine kinase, which is activated by chromosomal rearrangements or point mutations in multiple malignancies, including thyroid cancer. Selective RET inhibitors have proved their value in the treatment algorithm in molecularly selected patients with significantly high response rates and duration of response. Notwithstanding, there are patients who experiment rapid progression or tumor recurrence after an early response to those targeted therapies, which suggest the existence of primary and acquired mechanisms of resistance that have been largely unknown to date. In the present review, we attempt to provide a comprehensive analysis of the most relevant mechanisms of resistance to RET inhibitors which could help in the development of next generation MKI and RET inhibitors, along with combination strategies with different targeted therapies that could potentially overcome these resistances.

Outcomes of systemic targeted therapy in recurrent renal cell carcinoma treated with adjuvant sunitinib.

OBJECTIVE: To assess the efficacy and tolerability of rechallenge with sunitinib and other targeted therapies (TTs) in patitents with relapsed recurrent renal cell carcinoma (RCC) in the advanced setting. METHODS: In this multi-institutional retrospective study, patients with relapsed RCC were rechallenged with sunitinib or other systemic TTs as a first-line therapeutic approach after failed adjuvant sunitinib treatment. Patient characteristics, treatments and clinical outcomes were recorded. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR) and overall survival (OS). RESULTS: A total of 34 patients with relapses were recorded, and 25 of these (73.5%) were men. Twenty-five patients were treated with systemic TT: 65% of patients received TT against the vascular endothelial growth factor pathway (including sunitinib), 21.7% received mammalian target of rapamycin inhibitors and 13% received immunotherapy. The median (interquartile range) time to relapse was 20.3 (5.2-20.4) months from diagnosis, and 7.5 months (1.0-8.5) from the end of adjuvant suntinib treatment. At a median follow-up of 23.5 months, 24 of the 25 patients had progressed on first-line systemic therapy. The median PFS was 12.0 months (95% confidence interval [CI] 5.78-18.2). There were no statistical differences in PFS between different treatments or sunitinib rechallenge. PFS was not statistically different in patients relapsing on or after adjuvant suntinib treatment (≤ 6 or >6 months after adjuvant suntinib ending). The ORR was 20.5%. The median OS was 29.1 months (95% CI 16.4-41.8). CONCLUSIONS: Rechallenge with sunitinib or other systemic therapies is still a feasible therapeutic option that provides patients with advanced or metastastic RCC with additional clinical benefits with regard to PFS and OS after failed response to adjuvant sunitinib.