**Core Concept**
Methotrexate resistance is a significant clinical issue, especially in cancer treatment. It arises due to impaired cellular uptake, enhanced efflux, or altered metabolism of the drug. Methotrexate is a folate antagonist that inhibits dihydrofolate reductase (DHFR), a crucial enzyme in the synthesis of tetrahydrofolate.

**Why the Correct Answer is Right**
Methotrexate resistance can occur through several mechanisms, including the overexpression of the reduced folate carrier (RFC) or the folate receptor, which facilitate cellular uptake. However, one of the primary mechanisms is the overexpression of the multidrug resistance protein (MRP) or the P-glycoprotein (P-gp), which enhances efflux of the drug from the cell. This leads to decreased intracellular concentrations and reduced efficacy of methotrexate.

**Why Each Wrong Option is Incorrect**
* **Option A:** This option is incorrect because while impaired cellular uptake can contribute to methotrexate resistance, it is not the primary mechanism.
* **Option B:** This option is incorrect because altered metabolism of methotrexate is not a well-established mechanism of resistance.
* **Option C:** This option is incorrect because while the role of DHFR in methotrexate resistance is well understood, the overexpression of DHFR is not a primary mechanism of resistance.

**Clinical Pearl / High-Yield Fact**
Methotrexate resistance can be overcome by using high-dose regimens or by concomitantly administering leucovorin (folinic acid), which can bypass the impaired DHFR enzyme and restore methotrexate efficacy.

**Correct Answer:** C.