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Based on the timing and mechanisms of resistance development, resistance to targeted therapy can be categorized into two distinct types: primary resistance, defined by pre-existing genetic alterations or clonal heterogeneity that preclude initial response, and secondary resistance, which emerges following an initial therapeutic response due to drug pressure-driven clonal selection and adaptive phenotypic changes ( Tumor heterogeneity and clonal evolution represent the fundamental biological basis of targeted therapy resistance in RCC

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